Electrospun material covered medical appliances and methods of manufacture

ABSTRACT

A medical appliance or prosthesis may comprise one or more layers of electrospun nanofibers, including electrospun polymers. The electrospun material may comprise layers including layers of polytetrafluoroethylene (PTFE). Electrospun nanofiber mats of certain porosities may permit tissue ingrowth into or attachment to the prosthesis.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/827,790, filed on Mar. 14, 2013 and titled, “Electrospun MaterialCovered Medical Appliances and Methods of Manufacture,” which claimspriority to U.S. Provisional Application No. 61/703,037 filed on Sep.19, 2012 titled “Electrospun Material Covered Medical Appliances andMethods of Manufacture,” both of which are hereby incorporated byreference in their entireties.

TECHNICAL FIELD

The present disclosure relates generally to medical devices. Morespecifically, the present disclosure relates to medical appliances orother prostheses, particularly those made of, constructed from, orcovered or coated with electrospun materials including polymers such aspolytetrafluoroethylene (PTFE).

BRIEF DESCRIPTION OF THE DRAWINGS

The embodiments disclosed herein will become more fully apparent fromthe following description and appended claims, taken in conjunction withthe accompanying drawings. These drawings depict only typicalembodiments, which will be described with additional specificity anddetail through use of the accompanying drawings in which:

FIG. 1 is a schematic illustration of one embodiment of anelectrospinning apparatus.

FIG. 2 is a schematic illustration of another embodiment of anelectrospinning apparatus.

FIG. 3A is a perspective view of a covered stent.

FIG. 3B is a cross-sectional view of the covered stent of FIG. 3A takenthrough line 3B-3B.

FIG. 4A is a perspective view of an electrospun covering on a mandrel.

FIG. 4B is a perspective view of the covering of FIG. 4A partiallyremoved from the mandrel.

FIG. 4C is a perspective view of the covering of FIG. 4A repositioned onthe mandrel.

FIG. 4D is a perspective view of a scaffolding structure wound aroundthe covering and mandrel of FIG. 4C.

FIG. 4E is a perspective view of the scaffolding structure of FIG. 4Dwith a second electrospun covering.

FIG. 5 is a perspective view of a covered stent including cuffs.

FIG. 6 is a front view of a medical appliance frame structure.

FIG. 7A is a detail view of a portion of the frame of FIG. 6.

FIG. 7B is a detail view of an end of the frame of FIG. 6.

FIG. 7C is an alternative configuration of a portion of the frame ofFIG. 6.

FIG. 8 is an end view of a frame having flared ends.

FIG. 9 is a front view of a frame having flared ends.

FIG. 10 is a front view of a wire being shaped to form a frame.

FIG. 11A is a cross-sectional view of two body lumens with a stentdisposed therein.

FIG. 11B is a side view of a portion of a stent comprising a taperedsegment.

FIG. 11C is a side view of another embodiment of a stent comprising atapered segment.

FIG. 12A is an SEM (scanning electron micrograph) (950×) of a matelectrospun from a first polymer dispersion.

FIG. 12B is an SEM (950×) of a mat electrospun from a second polymerdispersion.

FIG. 12C is an SEM (950×) of a mat electrospun from a third polymerdispersion.

FIG. 12D is an SEM (950×) of a mat electrospun from a fourth polymerdispersion.

FIG. 12E is an SEM (950×) of a mat electrospun from a fifth polymerdispersion.

FIG. 13A is an SEM (950×) of a mat electrospun from a first polymerdispersion-water mixture.

FIG. 13B is an SEM (950×) of a mat electrospun from a second polymerdispersion-water mixture.

FIG. 13C is an SEM (950×) of a mat electrospun from a third polymerdispersion-water mixture.

FIG. 13D is an SEM (950×) of a mat electrospun from a fourth polymerdispersion-water mixture.

FIG. 13E is an SEM (950×) of a mat electrospun from a fifth polymerdispersion-water mixture.

FIG. 13F is an SEM (950×) of a mat electrospun from a sixth polymerdispersion-water mixture.

FIG. 13G is an SEM (950×) of a mat electrospun from a seventh polymerdispersion-water mixture.

FIG. 13H is an SEM (950×) of a mat electrospun from an eighth polymerdispersion-water mixture.

FIG. 14A is an SEM (180×) of a cooked, electrospun fluorinated ethylenepropylene (FEP) coating over an electrospun PTFE layer.

FIG. 14B is an SEM (950×) of the construct of FIG. 13A.

FIG. 15 is a graph showing average inflammatory score (H-Score=0-300) ofvarious PTFE materials following 2 weeks of subcutaneous implantation ina mouse model.

FIG. 16 is a graphical representation of the differences in cellularpenetration between electrospun PTFE and expanded PTFE (ePTFE)materials. Percent of cellular penetration is shown on the y-axis.

FIG. 17 is a representative trichrome-stained histology light microscopyimage of electrospun PTFE material (MM1 E-OD). Relative distance of cellpenetration is marked by the double black arrow. The dashed linescircumscribe the middle layer of the electrospun PTFE material. (Scalebar=100 um.)

DETAILED DESCRIPTION

Medical appliances may be deployed in various body lumens for a varietyof purposes. Stents may be deployed, for example, in the central venoussystem for a variety of therapeutic purposes including the treatment ofocclusions within the lumens of that system. The current disclosure maybe applicable to stents or other medical appliances designed for thecentral venous (CV) system, peripheral vascular (PV) stents, abdominalaortic aneurism (AAA) stents, bronchial stents, esophageal stents,biliary stents, coronary stents, gastrointestinal stents, neuro stents,thoracic aortic endographs, or any other stent or stent graft. Further,the present disclosure may be equally applicable to other prosthesessuch as grafts. Any medical appliance comprised of materials hereindescribed may be configured for use or implantation within various areasof the body, including vascular, cranial, thoracic, pulmonary,esophageal, abdominal, or ocular application. Examples of medicalappliances within the scope of this disclosure include, but are notlimited to, stents, vascular grafts, stent grafts, cardiovascularpatches, reconstructive tissue patches, hernia patches, general surgicalpatches, heart valves, sutures, dental reconstructive tissues, medicaldevice coverings and coatings, gastrointestinal devices, blood filters,artificial organs, ocular implants, and pulmonary devices, includingpulmonary stents. For convenience, many of the specific examplesincluded below reference stents. Notwithstanding any of the particularmedical appliances referenced in the examples or disclosure below, thedisclosure and examples may apply analogously to any prosthesis or othermedical appliance.

As used herein, the term “stent” refers to a medical applianceconfigured for use within a bodily structure, such as within a bodylumen. A stent may comprise a scaffolding or support structure, such asa frame, and/or a covering. Thus, as used herein, “stent” refers to bothcovered and uncovered scaffolding structures.

It will be readily understood that the components of the embodiments asgenerally described and illustrated in the Figures herein could bearranged and designed in a wide variety of different configurations.Thus, the following more detailed description of various embodiments, asrepresented in the Figures, is not intended to limit the scope of thedisclosure, but is merely representative of various embodiments. Whilethe various aspects of the embodiments are presented in drawings, thedrawings are not necessarily drawn to scale unless specificallyindicated.

The phrases “connected to,” “coupled to,” and “in communication with”refer to any form of interaction between two or more entities, includingmechanical, electrical, magnetic, electromagnetic, fluid, and thermalinteraction. Two components may be coupled to each other even thoughthey are not in direct contact with each other. For example, twocomponents may be coupled to each other through an intermediatecomponent.

The directional terms “proximal” and “distal” are used herein to referto opposite locations on a stent or another medical appliance. Theproximal end of an appliance is defined as the end closest to thepractitioner when the appliance is disposed within a deployment devicethat is being used by the practitioner. The distal end is the endopposite the proximal end, along the longitudinal direction of theappliance, or the end furthest from the practitioner. It is understoodthat, as used in the art, these terms may have different meanings oncethe appliance is deployed (i.e., the “proximal” end may refer to the endclosest to the head or heart of the patient depending on application).For consistency, as used herein, the ends labeled “proximal” and“distal” prior to deployment remain the same regardless of whether theappliance is deployed. The longitudinal direction of a stent is thedirection along the axis of a generally tubular stent. In embodimentswhere a stent or another appliance is composed of a metal wire structurecoupled to one or more layers of a film or sheet-like components, suchas a polymer layer, the metal structure is referred to as the“scaffolding” or “frame” and the polymer layer as the “covering” or“coating.” The terms “covering” or “coating” may refer to a single layerof polymer, multiple layers of the same polymer, or layers comprisingdistinct polymers used in combination. Furthermore, as used herein, theterms “covering” and “coating” refer only to a layer or layers that arecoupled to a portion of the scaffold; neither term requires that theentire scaffold be “covered” or “coated.” In other words, medicalappliances wherein a portion of the scaffold may be covered and aportion remain bare are within the scope of this disclosure. Finally,any disclosure recited in connection with coverings or coatings mayanalogously be applied to medical devices comprising one or more“covering” layers with no associated frame or other structure. Forexample, a hernia patch comprising any of the materials described hereinas “coatings” or “coverings” is within the scope of this disclosureregardless of whether the patch further comprises a frame or otherstructure.

Medical device coverings may comprise multilayered constructs, comprisedof two or more layers which may be serially applied. Further,multilayered constructs may comprise nonhomogeneous layers, meaningadjacent layers have differing properties. Thus, as used herein, eachlayer of a multilayered construct may comprise a distinct layer, eitherdue to the distinct application of the layers or due to differingproperties between layers.

Additionally, as used herein, “tissue ingrowth” and “cellularpenetration” refer to any presence or penetration of a biological orbodily material into a component of a medical appliance. For example,the presence of body tissues (e.g., collagen, cells, and so on) withinan opening or pore of a layer or component of a medical appliancecomprises tissue ingrowth into that component. Further, as used herein,“attachment” of tissue to a component of a medical appliance refers toany bonding or adherence of a tissue to the appliance, includingindirect bonds. For example, tissue of some kind (e.g., collagen) maybecome attached to a stent covering (including attachment via tissueingrowth) and another layer of biologic material (such as endothelialcells) may, in turn, adhere to the first tissue. In such instances, thesecond biologic material (endothelial cells in the example) and thetissue (collagen in the example) are “attached” to the stent covering.

Furthermore, through the present disclosure, certain fibrous materials(such as electrospun materials) may be referred to as inhibiting orpromoting certain biological responses. These relative terms areintended to reference the characteristics of the fibrous materials withrespect to non-fibrous materials or coatings. Examples of non-fibrouscoatings include non-fibrous polytetrafluoroethylene (PTFE) sheets,other similarly formed polymers, and the like. Mats or other structurescomprised of serially deposited fibers, such as microfibers and/ornanofibers are also examples of fibrous materials within the scope ofthis disclosure.

Serially deposited fiber mats or lattices refer to structures composedat least partially of fibers successively deposited on a collector, on asubstrate, on a base material, and/or on previously deposited fibers. Insome instances the fibers may be randomly disposed, while in otherembodiments the alignment or orientation of the fibers may be somewhatcontrolled or follow a general trend or pattern. Regardless of anypattern or degree of fiber alignment, because the fibers are depositedon the collector, substrate, base material, and/or previously depositedfibers, the fibers are not woven, but rather serially deposited. Becausesuch fibers are configured to create a variety of structures, as usedherein, the terms “mat” and “lattice” are intended to be broadlyconstrued as referring to any such structure, including tubes, spheres,sheets, and so on. Furthermore, the term “membrane” as used hereinrefers to any structure comprising serially deposited fibers having athickness which is smaller than at least one other dimension of themembrane. Examples of membranes include, but are not limited to,serially deposited fiber mats or lattices forming sheets, strips, tubes,spheres, covers, layers, and so forth. Examples of serially depositedfibers include electrospun fibers and rotational spun fibers. ExpandedPTFE does not comprise serially deposited fibers as used herein.

Lumens within the circulatory system are generally lined with a singlelayer (monolayer) of endothelial cells. This lining of endothelial cellsmakes up the endothelium. The endothelium acts as an interface betweenblood flowing through the lumens of the circulatory system and the innerwalls of the lumens. The endothelium, among other functions, reduces orprevents turbulent blood flow within the lumen. The endothelium plays arole in many aspects of vascular biology, including atherosclerosis,creating a selective barrier around the lumen, blood clotting,inflammation, angiogenesis, vasoconstriction, and vasodilation.

A therapeutic medical appliance that includes a covering of porous orsemi-porous material may permit the formation of an endothelial layeronto the porous surface of the blood contact side of the medical device.Formation of an endothelial layer on a surface, or endothelialization,may increase the biocompatibility of an implanted device. For example, astent that permits the formation of the endothelium on the insidediameter (blood contacting surface) of the stent may further promotehealing at the therapeutic region and/or have longer term viability. Forexample, a stent coated with endothelial cells may be more consistentwith the surrounding body lumens, thereby resulting in less turbulentblood flow or a decreased risk of thrombosis, or the formation of bloodclots. A stent that permits the formation of an endothelial layer on theinside surface of the stent may therefore be particularly biocompatible,resulting in less trauma at the point of application, fewer sideeffects, and/or longer term device viability. Medical appliancesincluding a covering of porous or semi-porous material may be configuredto inhibit or reduce inflammatory responses by the body toward thetissue contacting side of the medical appliance, for example. Mechanismssuch as an inflammatory response by the body toward the medicalappliance may stimulate, aggravate, or encourage negative outcomes, suchas neointimal hyperplasia. For example, a device configured to permittissue ingrowth and/or the growth or attachment of endothelial cellsonto the blood contacting side of the device may reduce the likelihoodof negative flow characteristics and blood clotting. Similarly, a deviceso configured may mitigate the body's inflammatory response toward thematerial on, for example, the tissue or non-blood contacting side of thedevice. By modulating the evoked inflammatory response, negativeoutcomes such as the presence of bioactive inflammatory macrophages andforeign body giant cells may be reduced. This may aid in minimizing thechemical chain of responses that may encourage fibrous capsule formationsurrounding the device and events stimulating neointimal hyperplasia.

Electrospun materials, such as those described herein, may be used tocomprise portions of medical appliances, such as stents, patches,grafts, and so forth. The present disclosure is applicable to anyimplantable medical appliance, notwithstanding any specific examplesincluded below. In other words, though particular medical appliances,such as stents or patches, may be referenced in the disclosure andexamples below, the disclosure is also analogously applicable to othermedical appliances, such as those that comprise a covering or layer ofpolymeric material.

In some embodiments, electrospun nanofibers (and/or microfibers) may beconfigured to permit interaction with nanoscale (and/or microscale) bodystructures, such as endothelial cells. Electrospinning refers generallyto processes involving the expulsion of flowable material from one ormore orifices, the material forming fibers that are subsequentlydeposited on a collector, and wherein there is an electrostatic chargebetween any of the collector, the material, and the orifice. Examples offlowable materials include dispersions, solutions, suspensions, liquids,molten or semi-molten material, and other fluid or semi-fluid materials.

For example, one embodiment of an electrospinning process comprisesloading a polymer solution or dispersion into a syringe coupled to asyringe pump. The material is forced out of the syringe by the pump inthe presence of an electric field. The material forced from the syringemay elongate into fibers that are then deposited on a groundedcollection apparatus. The system may be configured such that thematerial forced from the syringe is electrostatically charged, and thusattracted to the grounded collector. Exemplary methods and systems forelectrospinning medical devices can be found in U.S. patent applicationSer. No. 13/360,444, filed on Jan. 27, 2012 and titled “Electrospun PTFECoated Stent and Method of Use,” which is hereby incorporated byreference in its entirety.

Electrospinning may be configured to create mats, tubes, or otherstructures comprised of elongate fibers, including nanofibers (i.e.,fibers that are smaller than 1 micron in diameter) or microfibers (i.e.,fibers that are between 1 micron and 1 millimeter in diameter). In someinstances the fibers may be randomly disposed, while in otherembodiments the alignment or orientation of the fibers may be somewhatcontrolled or follow a general trend or pattern. Regardless of anypattern or degree of fiber alignment, as the fibers are deposited on acollector or on previously deposited fibers, the fibers are not woven,but rather are serially deposited on the collector or other fibers.Because electrospinning may be configured to create a variety ofstructures, as used herein, the terms “mat” and “non-woven mat ormaterial” are intended to be broadly construed as referring to any suchelectrospun structure, including tubes, spheres, and so on.

The present disclosure relates to medical appliances that may have, incertain embodiments, metal scaffolding covered with at least one layerof electrospun material, such as electrospun PTFE. Additionally, thepresent disclosure relates to medical appliances formed of electrospunmaterials that may not have scaffolding structures or have scaffoldingstructures that are not made of metal. It will be appreciated that,though particular structures and coverings are described below, anyfeature of the scaffolding or covering described below may be combinedwith any other disclosed feature without departing from the scope of thecurrent disclosure.

FIGS. 1 and 2 schematically illustrate certain embodiments ofelectrospinning apparatuses. FIGS. 3A and 3B illustrate an embodiment ofa covered medical appliance. FIGS. 4A-4E illustrate certain steps in aprocess of manufacturing a multi-layered construct of electrospunmaterials. FIG. 5 illustrates an embodiment of a medical appliance thatincludes cuffs at each end of a stent. FIGS. 6-10 illustrate aspects offrames configured for use in connection with medical appliances.Finally, FIGS. 11A-12H are scanning electron micrographs (SEMs) ofexemplary electrospun materials. Again, regardless of whether a medicalappliance illustrated in any particular figure is illustrated with aparticular covering or coating, or without any covering or coating atall, any embodiment of a medical appliance may be configured with any ofthe combinations of coverings or coatings shown or described herein.

Again, electrospinning generally references to processes configured todeposit fibers (including microfibers and nanofibers) on a collectionapparatus in the presence of an electric field. Variations in thematerial to be electrospun (including density, viscosity, composition,and so forth) as well as variations in the electric field or otherparameters of the electrospinning apparatus may be used to control oraffect the deposition of fibers on the collector.

Membranes composed of electrospun PTFE or other materials may have amicrostructure composed of numerous fibers crossing each other atvarious and random points. The electrospinning process may be configuredto control the thickness of the mat, the density of the fiber pattern,the thickness of the fibers, the permeability of the mat, and so forth.In some instances, a thicker mat may tend to be less permeable, due tosuccessive layers of fibers occluding the pores and openings of layersbelow.

FIG. 1 illustrates an electrospinning apparatus 100. This Figure, aswell as FIG. 2, discussed below, is intended to schematically illustratethe operation of an electrospinning apparatus, and is not meant to limitthe particular structure, shape, or arrangement of any electrospinningapparatus components within the scope of this disclosure. Theillustrated apparatus 100 comprises a syringe 110 coupled to a syringepump 115. In other embodiments, other pumps or devices may be configuredto expel material from an orifice. A high voltage source 120 may be incommunication with the syringe 110. Material to be electrospun may bedischarged from the syringe 110 through operation of the syringe pump115, and deposited on a collector 125. In the illustrated embodiment,the collector is grounded, thus creating an electrostatic potentialbetween the high voltage source (and components in communicationtherewith) and the collector 125. Material discharged from the syringe110 may form fibers 130 that are subsequently deposited on the collector125. In some embodiments, the fibers 130 may be charged with respect tothe grounded collector 125, and thus attracted to the collector 125 byelectrostatic forces.

In one exemplary procedure, the syringe 110 may be loaded with a polymerdispersion and the syringe pump 115 configured to disburse the materialat a constant rate. In one exemplary procedure this rate was set at 0.1ml of material per minute. The syringe 110 was configured with a metaltip that was connected to the positive lead of the high voltage source120. The collector 125 was placed about 7 inches from the syringe tip,and grounded. The voltage differential contributed in forcing thematerial from the syringe 110 to the collector 125 in nanoscale fibers.

The apparatus 100 may be utilized to create a mat of electrospun fibersdeposited on the collector 125. In the illustrated embodiment, thecollector 125 comprises a flat plate. In other embodiments, thecollector may comprise other shapes, such as rods, spheres, curvedsurfaces, and so forth. Thus, in some embodiments, the collector 125 maybe configured such that structures such as rods, tubes, or spheres ofelectrospun fibers are created.

In some embodiments, the apparatus 100 may be utilized to create a matof electrospun fibers by first filling the syringe 110 with a flowablematerial. In some instances polymer dispersions, including aqueousdispersions or polymer solutions, may be used. The syringe pump 115 maythen be operated such that the dispersion, or other flowable material,is forced out of the syringe 110. Molecules, including polymer chains,may tend to disentangle and/or align as the material is forced throughan orifice of the syringe 110. In some embodiments the orifice of thesyringe 110 may comprise a cannula configured with a quick connection,such as a luer connection, allowing for rapid exchange of variouscannula sizes.

As the dispersion is expelled from the syringe 110, the stream or jet ofmaterial may elongate, forming a relatively small diameter fiber ofmaterial. Further, in some embodiments, the material may be electricallycharged with respect to the collector 125. Thus, the material may bedrawn to the collector 125 by electrostatic forces. The electrostaticforces may tend to stretch and/or elongate the material as the fibers130 begin to form. The electrostatic forces may further affect thedeposition of the fibers 130 on the collector 125. In some embodiments,the strength of the electrostatic field may be varied in connection withcontrolling the deposition of fibers 130 on the collector 125.

Additionally, certain components of the dispersion, such as thedispersion medium or solvent, may partially or fully evaporate as thematerial is drawn into the fibers 130. In embodiments utilizing flowablematerials that have no solvent, such as molten material, there may be noevaporation as the material is drawn into the fibers 130.

Thus, the fibers 130 eventually contact, and are deposited on, thecollector 125. The electrostatic forces, as well as the inertia of thematerial discharged from the syringe 110 and/or other forces such asdrag on the fibers 130, may interact as the fibers 130 are deposited,causing the fibers 130 to be disposed in random patterns on thecollector 125. In some embodiments, air currents may be introduced (forexample through the use of fans) to partially control the deposition ofthe fibers 130 on the collector 125.

In embodiments utilizing certain flowable materials, the fibers 130 maythen be removed from the collector 125 and sintered, or sintered andthen removed. For example, sintering may be applicable to PTFE fibers,including PTFE fibers electrospun from a dispersion. The sinteringprocess may set or bond the structure of the mat and remove anyremaining water or other dispersion medium or solvent.

In some embodiments, the mat may be treated at a first temperature toremove solvents and a second temperature to sinter the mat. For example,a PTFE mat spun from an aqueous dispersion may be first treated at atemperature below the sintering temperature of PTFE in order to removeany remaining water. For example, the mat may be heated to about 200degrees C. to remove any remaining water in the mat. Further, othermaterials such as solvents or fiberizing agents may be evaporated orotherwise driven off at this stage. In some embodiments—as furtherdetailed below—a PTFE dispersion may be mixed with polyethylene oxide(PEO) prior to electrospinning the mat. Treating the spun mat attemperatures such as 200 degrees C. may force off remaining PEO as wellas water. In some embodiments the PTFE mat may then be sintered at about385 degrees C. In other embodiments, PTFE sintering may be completed attemperatures from about 360 degrees C. to about 400 degrees C., and/orat temperatures in excess of the crystalline melting point of the PTFE(about 342 degrees C.). In other instances the mat may only be heated tothe sintering temperature, removing the remaining water and/or PEO whilesimultaneously sintering the PTFE. Additionally or alternatively, insome embodiments solvents or other materials may be removed by rinsingthe mat.

Sintering may set the structure of the mat even if the temperature atwhich the material is sintered is not sufficient to cause cross-linkingof the polymer chains. PTFE sintering may create solid, void-free, PTFEfibers.

The distance between the syringe 110 and the collector 125 may impactthe diameter of the fibers 130 and/or the deposition of the fibers 130on the collector 125. In some embodiments, variations to the degree ofthe electrostatic potential between these components may also impact thefiber diameter in connection with the distance between components.

Processes such as the exemplary process described above may be utilizedto create structures comprised of small diameter fibers, includingnanofibers. The fiber mat may then be incorporated into a medicalappliance configured for implantation in the human body. Some suchstructures, including nanofiber structures, may be configured to permittissue ingrowth and/or endothelial growth or attachment on the mat. Forexample, the mat may be configured with openings within the fibers orsimilar structures configured to permit interaction with tissue and/orcells. As further detailed below, the percent porosity of a fiber mat,the thickness of the mat, and the diameter of the fibers comprising themat may each be configured to create a fiber mat with desiredproperties, including mats that tend to permit or resist tissue ingrowthand/or endothelial growth or attachment.

A number of variables may be controlled to affect the properties of anelectrospun mat. Some of these variables include the strength of theelectrostatic charge; the viscosity of the solution, dispersion, orother flowable material; the temperature of the syringe 110; introducedair currents; the thickness of the mat; and so on. In the case of fiberselectrospun from molten material, the melt flow index (MFI) of thematerial may also impact the nature of the spun mat. In someembodiments, materials with an MFI of from about 1 g/10 min to about5000 g/10 min, including from about 200 g/10 min to about 1500 g/10 minand from about 10 g/10 min to about 30 g/10 min, may tend to form fiberswhen spun.

In other embodiments an electrospun mat may be configured to resisttissue ingrowth into or through the mat. In such embodiments, the matmay be configured with very small pores, or essentially no pores at all,thus preventing tissue ingrowth into or through the mat. Certain medicalappliances may be constructed partially of electrospun materialsconfigured to permit tissue ingrowth and/or endothelial growth orattachment and partially of electrospun materials configured to resisttissue ingrowth and/or attachment. Characteristics of the electrospunfiber mat, such as porosity and average pore size, may be controlledduring the electrospinning process to create certain mats that permittissue ingrowth and/or endothelial growth or attachment and other matsthat resist or are impermeable to tissue ingrowth and/or attachment.

In some embodiments, a PTFE dispersion may be used to electrospin a mator another structure comprised of PTFE nanofibers. Furthermore, in someexemplary embodiments PEO may be added to the PTFE dispersion prior toelectrospinning the material. The PEO may be added as a fiberizingagent, to aid in the formation of PTFE fibers within the dispersion orduring the process of electrospinning the material. In some instancesthe PEO may more readily dissolve in the PTFE dispersion if the PEO isfirst mixed with water. In some examples this increased solubility mayreduce the time needed to dissolve PEO in a PTFE dispersion from as longas multiple days to as little as 30 minutes. After the material iselectrospun onto a collector, the material may then be sintered asfurther described below. In some instances the sintering process willtend to set or harden the structure of the PTFE. Furthermore, asdescribed above, sintering may also eliminate the water and PEO,resulting in a mat of substantially pure PTFE. Additionally, as alsodescribed above, the mat may first be heat treated at a temperaturebelow the sintering temperature of the PTFE, in order to remove waterand/or PEO from the mat. In some embodiments this step may be completedat about 200 degrees C.

The water, PEO, and PTFE amounts may be controlled to optimize theviscosity, PEO/PTFE ratio, or other properties of the mixture. In someinstances adding water to the PEO before mixing with the PTFE dispersionmay aid in reducing the number of solid chunks or gels in the mixture,lower the preparation time for the mixtures, and reduce the time neededfor the combined mixture to solubilize.

In one exemplary process, a 60 wt % PTFE water dispersion was mixed withPEO and water as follows. First, 5 ml of water was added to 1.4 g ofPEO. The water and PEO were mixed until the PEO was fully dissolved andthe solution created a thick gel. 30 ml of 60 wt % PTFE was then addedto the PEO/water mixture. The combined solution was then allowed to sitor mix in a non-agitating jar roller until the solution achievedhomogeneity. In other examples, the water, PEO, and PTFE amounts may becontrolled to optimize the viscosity, PEO/PTFE ratio, or otherproperties of the mixture. In some instances adding water to the PEObefore mixing with the PTFE dispersion may aid in reducing the number oflarge solid chunks in the mixture, lower the preparation time for themixtures, and reduce the time needed for the combined mixture tosolubilize. In other embodiments each of these materials, orsub-combinations thereof, may be placed in a jar roller for about threeto about five days, after which time the mixture may be filtered througha 5 micron filter. Filtration may remove and/or break up any chunks orgels in the mixture. Other filters, for example 1 micron filters, maylikewise be used.

A variety of materials may be electrospun to form structures for use inmedical appliances. Exemplary materials that may be electrospun for usein implantable appliances include PTFE, fluorinated ethylene propylene(FEP), Dacron or polyethylene terephthalate (PET), polyurethanes,polycarbonate polyurethanes, polypropylene, Pebax, polyethylene,biological polymers (such as collagen, fibrin, and elastin), andceramics.

Furthermore, additives or active agents may be integrated with theelectrospun materials, including instances where the additives aredirectly electrospun with other materials. Such additives may includeradiopaque materials such as bismuth oxide, antimicrobial agents such assilver sulfadiazine, antiseptics such as chlorhexidine or silver, andanticoagulants such as heparin. Organic additives or components mayinclude fibrin and/or collagen. In some embodiments, a layer of drugs orother additives may be added to an electrospun appliance duringmanufacture. Additionally, some appliances may be constructed with acombination of synthetic components, organic components, and/or activeingredients including drugs, including embodiments wherein an applianceis comprised of alternating layers of these materials. Moreover, in someembodiments a medical appliance may consist of layers of electrospunmaterials configured to control the release of a drug or another activelayer disposed between such layers. Active layers or ingredients such asdrugs or other active agents may be configured to reduce or otherwisemodify or influence the biological response of the body to theimplantation of the medical appliance.

Additionally, in some embodiments the material supplied to the syringe110 may be continuously supplied (for example by a feed line), includingembodiments where the syringe 110 is pressurized or supplied by apressurized source. Additionally, other discharge mechanisms (such as apump) may be used to discharge material to be electrospun. Further, insome embodiments the material may be heated near or above its meltingpoint prior to electrospinning, including embodiments wherein thematerial is melted and not dispersed in a solvent. Thus, in someembodiments, electrospinning molten material does not include the use ofsolvents; therefore there is no need to remove solvents from the mat ata later step in the process. In some instances the material may besupplied to the syringe or other reservoir as pellets that are heatedand melted within the reservoir.

Another schematic embodiment of an electrospinning apparatus is shown inFIG. 2. It shows an apparatus 200, analogous to that shown in FIG. 1. Itwill be appreciated by one of skill in the art having the benefit ofthis disclosure that analogous components of the two apparatuses may beinterchangeable and that disclosure provided in connection with eachembodiment may be applicable to the other and vice versa.

FIG. 2 is a schematic diagram of an electrospinning apparatus 200comprising a syringe 210 coupled to a syringe pump 215. A high voltagesource 220 may be in communication with the syringe 210. Material to beelectrospun may be discharged from the syringe 210 through operation ofthe syringe pump 215, and deposited on a collector 225. As with theembodiment of FIG. 1, in the embodiment of FIG. 2, the collector isgrounded, thus creating an electrostatic potential between the highvoltage source 220 (and components in communication therewith) and thecollector 225. Material discharged from the syringe 210 may form fibers230 that are subsequently deposited on the collector 225. Again, in someembodiments, the fibers 230 may be charged with respect to the groundedcollector 225, and thus attracted to the collector 225 by electrostaticforces.

As compared to the apparatus 100 of FIG. 1, in the embodiment of FIG. 2the collector 225 comprises a rotating mandrel 226 as opposed to a flatplate. In other embodiments, other shapes or types of collectors may beused. Thus, any collection device or apparatus is within the scope ofthis disclosure, regardless of the particular size, shape, ororientation of the collector. In some embodiments, a collector maycomprise multiple elements, such as multiple cylinders or plates. Instill other embodiments, the collector may comprise a rotating belt (notshown), configured to facilitate electrospinning of a continuous sheetof material.

In the embodiment of FIG. 2, the collector 225 comprises a mandrel 226that may be configured to rotate about its longitudinal axis. Inembodiments wherein such a mandrel is configured to rotate during theelectrospinning process, the system may be configured to produce aseamless tube of electrospun material on the mandrel 226. Additionally,some embodiments may comprise more than one mandrel for use inconnection with the electrospinning system. In the illustratedembodiment, the mandrel 226 is disposed horizontally. In anotherexemplary embodiment, the mandrel 226 may be disposed vertically. Insome embodiments, the rotational speed of the mandrel 226 may affect thedegree to which fibers deposited thereon tend to be aligned.

In addition to horizontal mandrels, further embodiments may comprisemandrels disposed in any relative position. Mandrels mounted in anydisposition may be configured as stationary collection devices orconfigured to rotate. Additionally, combinations of mandrels in avariety of positions may be used simultaneously. Furthermore, in someembodiments one or more mandrels may be configured for use in connectionwith a vacuum system. For example, openings in the surface of themandrel, such a micro-porous mandrel, may tend to draw fibers toward themandrel in instances where the interior of the mandrel has lowerpressure than the exterior of the mandrel. Additionally, in someembodiments fans or other devices may be configured to create aircurrents to direct or otherwise influence the deposition of fibers onthe mandrel.

In embodiments wherein the mandrel 226 is configured to rotate, thespinning motion of each mandrel 226 may tend to deposit the fibers 230around the entire surface of the mandrel 226. Thus, as the fibers 230are deposited on the mandrel 226, a seamless tube of nanofiber materialmay form on the mandrel 226. The density of the fibers 230, thethickness of the mat, and other characteristics may be controlled bysuch variables as the distance from the syringe 210 to the mandrel 226,the magnitude of the electrostatic charge, the rotational speed of themandrel 226, the orientation of the mandrel 226, the characteristics ofthe solution being spun, and so forth. In some instances, mats ofelectrospun material formed on a spinning mandrel 226 may thus comprisea tubular membrane having no seam and substantially isotropicproperties. In some instances the collection mandrel 226 may rotate atrates between about 1 RPM and about 10,000 RPM during theelectrospinning process, including rates from about 1500 RPM to about5000 RPM or at about 5000 RPM for more aligned fibers and from about 50RPM to about 500 RPM or at about 250 RPM for more random fiberorientation.

Furthermore, controlling the rotational speed of the mandrel 226 mayinfluence both the density of the mat formed on the mandrel 226 and thegeneral alignment of the fibers 230 in the mat. For instance, in someembodiments utilizing vertical mandrels, the faster the mandrel 226 isspinning the more the fibers 230 may tend to be deposited in-line withother fibers 230. Further, the relative density of the fibers 230, forexample, as measured by percent porosity, may be controlled in part bythe rotational speed of the mandrel 226.

As further detailed in connection with FIGS. 4A-4E, once the fibers 230are electrospun onto the mandrel 226 the fibers 230 may be sintered. Insome embodiments a scaffolding structure, such as a stent wire, may alsobe on the mandrel 226, and the fibers 230 electrospun directly onto themandrel 226 and scaffolding structure.

In addition to mandrels, some systems may be configured to form acontinuous sheet of electrospun material, including mats from about 1meter to about 9 meters wide, such as mats of about 3 meters wide. Alsomats from about 1 foot wide to about 1 meter wide (as well as larger orsmaller mats) may be formed. In some instances, a sintering oven may bepositioned such that as the mat moves away from the electrospinningapparatus (for example, on the belt) the mat enters the oven and issintered. The sintered mat may then be collected onto a spool. Further,in some embodiments, the entire spool may then be cut into smallerwidths, forming strips of material. For example, strips from about 0.1inch wide to about 2 inches wide may be formed. Additionally, smallerstrips, for example about 0.1 inch wide, or larger strips, for exampleabout 12 inches wide, may be formed. Such strips may be utilized for theconstruction of tubular appliances by wrapping the strips around amandrel. The strips may overlap and/or may be wound such that the tubeformed does not have a distinct seam along the length of the tube. Insome instances, the mat may be wound in multiple layers around themandrel. Further, the mat formed may be relatively thin, or film-like.The thickness of the covering formed on the mandrel (and othercharacteristics such as porosity) may be controlled by the number oflayers of film wound onto the mandrel. Film layers of differingmaterials may also be added to create a covering with particularproperties. For example, Kapton and/or FEP may be added to increasestrength in some instances.

In some embodiments, electrospun tubular medical devices, such asstents, may comprise one or multiple bifurcations or branches. Thus,medical devices that comprise a single lumen that splits or bifurcatesinto two or more lumens are within the scope of this disclosure.Likewise, medical appliances comprising a main lumen with one ormultiple branch lumens extending from the wall of the main lumen arewithin the scope of this disclosure. For example, a thoracicstent—configured for deployment within the aorta—may comprise a mainlumen configured to be disposed in the aorta and branch lumensconfigured to extend into side branch vessels originating at the aorta.Similarly, in some embodiments such stents may alternatively beconfigured with access holes in the main lumen configured to allowaccess (possibly for additional stent placement) and flow from the mainvessel to any branch vessels extending therefrom.

In some embodiments, a bifurcated medical appliance may be manufacturedby first creating a bifurcated mandrel in which the bifurcated mandrelportions are removable from the portion of the mandrel coinciding withthe main lumen. The leg or branch portions of the mandrel may be splayed180 degrees apart with a common axis of rotation. Thus, in someembodiments, the entire mandrel may form a T-shape. The entire mandrelmay then be rotated about the axis of the leg portions and electrospunfibers collected on the leg portions of the mandrel. The mandrel maythen be oriented to rotate about the axis of the main lumen portion ofthe mandrel, and any unwanted fibers disposed while spinning on thebifurcated leg portions may be wiped off. The mandrel may then berotated about the axis of the main lumen portion and fibers collected onthe main lumen portion of the mandrel. The entire mandrel may then beplaced in an oven and sintered. The mandrel portions associated with thebifurcated legs may then be removed from the leg or branch portions ofthe appliance, and the single lumen mandrel portion subsequently removedfrom the spun appliance. The appliance may then be placed on or within aframe structure, such as a stent frame. A dip, spray, or film coating(such as of FEP or PTFE) may then be applied over the construct tocreate an impervious layer and/or to further bond the frame to the spunportion of the appliance.

In any of the exemplary embodiments or methods disclosed herein, ininstances where the nanofibers are formed of PTFE, the sinteringtemperature may be from about 360 degrees C. to about 400 degrees C.,including at temperatures of about 385 degrees C. or at temperaturesabove the crystalline melting temperature of the PTFE, or about 342degrees C. Similarly, for other materials, sintering may be done at orabove the crystalline melting temperature of other spun polymers. Again,either prior to or as part of the sintering process, heat treating maybe configured to remove PEO and/or water, in instances where the PTFE orother polymer was combined with such elements prior to spinning the mat.

FIGS. 3A and 3B illustrate an exemplary medical appliance: a stent 302.The stent 302 comprises a scaffolding structure 320 and a coveringcomprising an inner layer 325, an outer layer 330, and a tie layer 335.In other embodiments, a stent covering may have more or fewer layersthan the illustrated embodiment, including embodiments with only onecovering layer. Again, disclosure recited herein with respect tospecific medical appliances, such as stents, may also be applicable toother medical appliances.

The cover of the stent 302 of FIG. 3A comprises a flat end 321 and ascalloped end 322. At the flat end 321 of the illustrated embodiment,the cover of the stent 302 is cut substantially perpendicular to thelongitudinal axis of the stent 302. At the scalloped end 322, the coverof the stent 302 comprises cut away, or scalloped, portions at the endof the stent 302. Scalloped ends may be configured to reduce infoldingof the stent cover at the ends. For example, in some instances, a stentmay have a larger diameter than a vessel in which it is deployed. Thus,the vessel may partially compress the stent radially. In some instancesthis radial compression may create folds or wrinkles in flat cut stentcovers. These folds may then impede blood flow or lead to clottingwithin the vessel. Scalloped ends may reduce the occurrence of infoldingat the end of a radially compressed stent. It is within the scope ofthis disclosure to use either type of end on any end of any stent.

Membranes composed of electrospun mats may have a microstructurecomposed of many fibers crossing each other at various and randompoints. The electrospinning process may control the thickness of thisstructure and thereby the relative permeability of the mat. As more andmore fibers are electrospun onto a mat, the mat may both increase inthickness and decrease in permeability (due to successive layers ofstrands occluding the pores and openings of layers below). Certaindetails of this microstructure are shown in FIGS. 11A-12H, which arediscussed in more detail below.

Mats produced in connection with the present disclosure may be describedby three general parameters: percent porosity, mat thickness, and fiberdiameter. Each of these parameters may impact the nature of the mat,including the tendency of the mat to permit tissue ingrowth and/orendothelial attachment or the tendency of the mat to resist tissueingrowth or endothelial attachment. Each of these parameters may beoptimized with respect to each other to create a mat having particularcharacteristics.

Percent porosity refers to the percent of open space to closed space (orspace filled by fibers) in a fiber mat. Thus, the more open the mat is,the higher the percent porosity measurement. In some instances, percentporosity may be determined by first obtaining an image, such as an SEM,of an electrospun material. The image may then be converted to a “binaryimage,” or an image showing only black and white portions, for example.The binary image may then be analyzed and the percent porositydetermined by comparing the relative numbers of each type of binarypixel. For example, an image may be converted to a black and white imagewherein black portions represent gaps or holes in the electrospun matwhile white portions represent the fibers of the mat. Percent porositymay then be determined by dividing the number of black pixels by thenumber of total pixels in the image. In some instances, a code or scriptmay be configured to make these analyses and calculations.

In some embodiments, percent porosities from about 30% to about 80% maybe configured to permit tissue ingrowth into the layer and/or permitendothelial growth or attachment on the layer, including mats of about40% to about 60%, mats of about 45% to about 50%, or mats of about 50%porosity. Less open layers may be configured to resist such ingrowthand/or attachment. Because the fibers comprising the mat are depositedin successive layers, the second parameter, mat thickness, may berelated to porosity. In other words, the thicker the mat, the morelayers of fibers and the less porous the mat may be. In someembodiments, mats from about 20 micrometers to about 100 micrometers maybe configured for use in connection with the present disclosure,including mats from about 40 micrometers to about 80 micrometers.Finally, the third parameter, fiber diameter, may be a measurement ofthe average fiber diameter of a sample in some instances. In someembodiments fiber diameters from about 50 nanometers to about 3micrometers may be used in connection with the present disclosure.Notwithstanding these or other specific ranges included herein, it iswithin the scope of this disclosure to configure a mat with anycombination of values for the given parameters.

In some embodiments the “average pore size” of the mat may be used as analternative or additional measurement of the properties of the mat. Thecomplex and random microstructure of electrospun mats presents achallenge to the direct measurement of the average pore size of the mat.Average pore size can be indirectly determined by measuring thepermeability of the mat to fluids using known testing techniques andinstruments. Once the permeability is determined, that measurement maybe used to determine an “effective” pore size of the electrospun mat. Asused herein, the “pore size” of an electrospun mat refers to the poresize of a membrane that corresponds to the permeability of theelectrospun mat when measured using ASTM standard F316 for thepermeability measurement. This standard is described in ASTM publicationF316, “Standard Test Methods for Pore Size Characteristics of MembraneFilters by Bubble Point and Mean Flow Pore Test,” which is incorporatedherein by reference. In some instances this test can be used as aquality control after configuring a mat based on the three parameters(percent porosity, thickness, and fiber diameter) discussed above.

In some applications it may be desirable to create a medical appliancesuch as stent 302 with an outer layer 330 that is substantiallyimpermeable. Such an impermeable outer layer 330 may decrease theincidence of lumen tissue surrounding the stent 302 growing into orattaching to the stent 302. This may be desirable in applications wherethe stent 302 is used to treat stenosis or other occlusions; animpermeable outer layer 330 may prevent tissue from growing into orthrough the material toward or into the lumen of the stent 302 andreblocking or restricting the body lumen. In some embodiments asubstantially impermeable outer layer 330 may be produced by usingelectrospun mats with a percent porosity from about 0% to about 50%,including about 25%; a thickness from about 20 micrometers to about 100micrometers, including from about 40 micrometers to about 80micrometers; and fiber diameters from about 50 nanometers to about 3micrometers.

Additionally, or alternatively, a substantially impermeable mat may havean average pore size of about 0 microns to about 1.5 microns. In otherembodiments, an impermeable layer may have an average pore size of lessthan about 0.5 micron. In yet other embodiments, an impermeable layermay have an average pore size of less than about 1 micron. In someembodiments, the impermeable layer may be a layer other than the outerlayer, such as a tie layer, an intermediate layer, or an inner layer.

In one example, a medical appliance such as stent 302 may be coveredwith an electrospun PTFE inner layer 325 and an electrospun PTFE outerlayer 330. The outer layer 330 may be configured to be substantiallyimpermeable to tissue ingrowth and/or attachment. In other embodimentsthe impermeability of the stent 302 may be provided by a tie layer 335disposed between the outer layer 330 and the inner layer 325. Forexample, a substantially impermeable layer may be formed of FEP that isapplied, for example, as a film, spray, or dip coating betweenelectrospun layers of PTFE. Furthermore, FEP may be electrospun with asmall average pore size to create a substantially impermeable layer. Insome embodiments both the outer layer 330 and the tie layer 335 may beconfigured to be substantially impermeable.

Dip coatings may be applied by dipping a portion of a layer or constructin a polymer dispersion. For example, a PTFE layer may be dip coated ona construct by adding 20 ml of water to 50 ml of a 60 wt % PTFEdispersion to thin the dispersion. A fiber mat may then be dipped in thesolution to coat the mat. The dip coat may then be sintered at 385degrees C. for 15 minutes. Other concentrations of PTFE dispersions fordip coatings are also within the scope of this disclosure.

Further, an FEP layer may be dip coated on a construct by adding 20 mlof water to 50 ml of a 55 wt % dispersion to thin the dispersion. Afiber mat may then be dipped in the solution to coat the mat. The dipcoat may then be cooked, for example, at 325 degrees C. for 15 minutes.Other concentrations of FEP dispersions for dip coatings are also withinthe scope of this disclosure. Additionally, polymer dispersions may besprayed or otherwise applied onto a surface (such as a fiber mat) tocoat the surface. Such coatings may be heat treated after application.

In some embodiments, more or less water, for example from about 10 ml toabout 50 ml, may be added to similar amounts and concentrations of thedip dispersions above to thin the dispersions. Additionally, substancesother than, or in addition to, water may be used to thin a dispersionfor dip coating. For example, a surfactant or a solvent may be used. Insome such cases the surfactant or solvent may later be removed from theconstruct, including embodiments where it is allowed to evaporate whenthe coat is sintered or cooked. Alcohols, glycols, ethers, and so forthmay be so utilized.

In some embodiments it may be desirable to create a medical appliancesuch as stent 302 with an outer layer 330 that is more porous. A porousouter layer 330 may permit healing and the integration of the prosthesisinto the body. For instance, tissue of the surrounding lumen may growinto the porous outer diameter or attach to the outer diameter layer.This tissue ingrowth may permit, modulate, and/or influence healing atthe therapy site. In some embodiments a porous outer layer 330 may beformed of electrospun PTFE.

In certain embodiments a relatively porous inner layer 325 may bedesirable. This layer may or may not be used in conjunction with asubstantially impermeable outer layer 330. A relatively porous innerlayer 325 may permit tissue ingrowth and/or endothelial attachment orgrowth on the inside diameter of the stent 302 that may be desirable forany combination of the following: healing, biocompatibility, preventionof thrombosis, and/or reducing turbulent blood flow within the stent. Insome embodiments the inner layer 325 may be comprised of a mat, such asan electrospun PTFE mat, having a percent porosity of about 40% to about80%, including about 50%; a thickness of about 20 micrometers to about100 micrometers, including from about 40 micrometers to about 80micrometers; and fiber diameters from about 50 nanometers to about 3micrometers.

Additionally, or alternatively, the mat may be comprised of anelectrospun mat, such as PTFE, with an average pore size of about 1micron to about 12 microns, such as from about 2 microns to about 8microns, about 3 microns to about 5 microns, or about 3.5 microns toabout 4.5 microns.

FIG. 3B illustrates a cross-sectional view of the stent 302 of FIG. 3A,again comprising a scaffolding structure 320 and covering comprising aninner layer 325, an outer layer 330, and a tie layer 335. Though in theillustration of FIG. 3B the tie layer 335 is shown at the same “level”as the scaffolding structure 320, the tie layer 335 may be above orbelow the scaffolding structure 320 in some embodiments. Further, asshown in FIG. 3B, each layer of the covering may be disposed so thatthere are no voids between layers.

In some embodiments the tie layer 335 may be configured to promotebonding between the outer layer 330 and the inner layer 325. In otherembodiments the tie layer 335 may further be configured to providecertain properties to the stent 302 as a whole, such as stiffness ortensile strength. The tie layer 335 may thus be configured as areinforcing layer. In some embodiments, expanded PTFE may be configuredas a reinforcing layer. ePTFE may be anisotropic, having differingproperties in differing directions. For example, ePTFE may tend toresist creep in the direction the ePTFE membrane was expanded. Areinforcing layer of ePTFE may be oriented to increase strength, resistcreep, or impart other properties in a particular direction. ePTFE maybe oriented such that the expanded direction is aligned with an axialdirection of a medical device, a transverse direction, a radialdirection, at any angle to any of these directions, and so forth.Similarly, multiple layers of ePTFE may be disposed to increasestrength, resist creep, or impart other properties in multipledirections. The reinforcing layer may or may not be impermeable.

Additionally, in embodiments where both the inner layer 325 and theouter layer 330 are porous in nature, the tie layer 335 may beconfigured to create an impermeable layer between the two porous layers.In such embodiments the stent 302 may permit tissue ingrowth, tissueattachment, and/or healing on both the inner and outer surfaces of thestent 302 while still preventing tissue outside of the stent 302 fromgrowing into the lumen and occluding the lumen. Thus, the tie layer 335may be configured to create a mid-layer portion of a construct, the tielayer 335 configured to inhibit tissue ingrowth into the layer or to beimpervious to tissue migration into or through the layer or tosubstantially inhibit tissue migration.

Furthermore, the tie layer 335 may be configured to be impervious orsubstantially impervious to fluid migration across the tie layer 335.Specifically, constructions comprising one or more porous layers mayallow fluid to cross the porous layer. In the case of a medicalappliance configured to control blood flow, such as a graft, a porouslayer may allow blood to leak across the layer or may allow certainsmaller components of the blood to cross the layer while containinglarger components, effectively filtering the blood. In some instancesthis filtration or ultrafiltration may allow components such as plasmato cross the barrier while containing red blood cells, leading toseroma. Thus, a fluid impermeable tie layer may be configured to containfluid within a medical device also comprised of porous layers. In somedevices, a tie layer may be both fluid impermeable and impervious totissue ingrowth, or may be configured with either of these propertiesindependent of the other. Constructs wherein any layer (other than, orin addition to, a tie layer) is configured to be fluid impermeableand/or impervious to tissue ingrowth are also within the scope of thisdisclosure. Thus, disclosure recited herein in connection with fluidimpermeable and/or tissue impervious tie layers may be analogouslyapplied to impermeable layers at various locations within a construct.

The tie layer (or any impermeable/impervious layer) may include anythermoplastic and may or may not be electrospun. In one embodiment, thetie layer may be ePTFE. In another it may be electrospun PTFE. In otherembodiments it may be FEP, including electrospun FEP and FEP applied asa film or dip coating. Furthermore, the tie layer may include any of thefollowing polymers or any other thermoplastic: dextran, alginates,chitosan, guar gum compounds, starch, polyvinylpyridine compounds,cellulosic compounds, cellulose ether, hydrolyzed polyacrylamides,polyacrylates, polycarboxylates, polyvinyl alcohol, polyethylene oxide,polyethylene glycol, polyethylene imine, polyvinylpyrrolidone,polyacrylic acid, poly(methacrylic acid), poly(itaconic acid),poly(2-hydroxyethyl acrylate), poly(2-(dimethylamino)ethylmethacrylate-co-acrylamide), poly(N-isopropylacrylamide),poly(2-acrylamido-2-methyl-1-propanesulfonic acid),poly(methoxyethylene), poly(vinyl alcohol), poly(vinyl alcohol) 12%acetyl, poly(2,4-dimethyl-6-triazinylethylene),poly(3morpholinylethylene), poly(N-1,2,4-triazolyethylene), poly (vinylsulfoxide), poly(vinyl amine), poly(N-vinyl pyrrolidone-co-vinylacetate), poly(g-glutamic acid), poly(Npropanoyliminoethylene),poly(4-amino-sulfo-aniline), poly [N-(psulphophenyl)amino-3-hydroxymethyl-1,4phenyleneimino-1,4-phenylene],isopropyl cellulose, hydroxyethyl, hydroxylpropyl cellulose, celluloseacetate, cellulose nitrate, alginic ammonium salts, i-carrageenan,N-[(3′-hydroxy-2′,3′-dicarboxy)ethyl]chitosan, konjac glocomannan,pullulan, xanthan gum, poly(allyammonium chloride), poly(allyammoniumphosphate), poly(diallydimethylammonium chloride),poly(benzyltrimethylammonium chloride),poly(dimethyldodecyl(2-acrylamidoethyly) ammonium bromide),poly(4-N-butylpyridiniumethylene iodine), poly(2-N-methylpridiniummethylene iodine), poly(N methylpryidinium-2,5-diylethenylene),polyethylene glycol polymers and copolymers, cellulose ethyl ether,cellulose ethyl hydroxyethyl ether, cellulose methyl hydroxyethyl ether,poly(I-glycerol methacrylate), poly(2-ethyl-2-oxazoline),poly(2-hydroxyethyl methacrylate/methacrylic acid) 90:10,poly(2-hydroxypropyl methacrylate),poly(2-methacryloxyethyltrimethylammonium bromide),poly(2-vinyl1-methylpyridinium bromide), poly(2-vinylpyridine N-oxide),poly(2-vinylpyridine), poly(3-chloro-2-hydroxypropyl2-methacryloxyethyldimethylammonium chloride), poly(4vinylpyridineN-oxide), poly(4-vinylpyridine), poly(acrylamide/2-methacryloxyethyltrimethylammonium bromide) 80:20,poly(acrylamide/acrylic acid), poly(allylamine hydrochloride),poly(butadiene/maleic acid), poly(diallyldimethylammonium chloride),poly(ethyl acrylate/acrylic acid), poly(ethylene glycol)bis(2-aminoethyl), poly (ethylene glycol) monomethyl ether,poly(ethylene glycol)bisphenol A diglycidyl ether adduct, poly(ethyleneoxide-bpropylene oxide), poly(ethylene/acrylic acid) 92:8, poly(llysinehydrobromide), poly(l-lysine hydrobromide), poly (maleic acid),poly(n-butyl acrylate/2methacryloxyethyltrimethylammonium bromide),poly(Niso-propylacrylamide), poly(N-vinylpyrrolidone/2dimethylaminoethylmethacrylate), dimethyl sulfatequaternary, poly(N-vinylpyrrolidone/vinylacetate), poly(oxyethylene) sorbitan monolaurate (Tween 20®), poly(styrenesulfonic acid), poly(vinyl alcohol),N-methyl-4(4′formylstyryl)pyridinium, methosulfate acetal, poly(vinylmethyl ether), poly(vinylamine) hydrochloride, poly(vinylphosphonicacid), poly(vinylsulfonic acid) sodium salt, and polyaniline.

Regardless of the material, the tie layer 335 may or may not beelectrospun. Further, in certain embodiments the stent 302 may includetwo or more tie layers 335. The tie layer 335 may be formed in anymanner known in the art and attached to the inner 325 and outer 330layers in any manner known in the art. For example, the tie layer 335may comprise a sheet of material that is wrapped around the inner layer325 or a tube of material that is slipped over the inner layer 325 thatis then heat shrunk or otherwise bonded to the inner 325 and outer 330layers. Further, in embodiments where the tie layer is electrospun, itmay be electrospun directly onto the inner layer 325, the scaffoldingstructure 320, or both. In some instances the tie layer 335 may bemelted after the stent 302 is constructed to bond the tie layer 335 toadjacent layers of the stent covering.

Furthermore, the tie layer may be configured to change the overallproperties of the medical appliance. For example, in some instances acover or construct comprised solely of electrospun PTFE (of the desiredpore size) may not have desired tensile or burst strength. A tie layercomprised of a relatively stronger material may be used to reinforce thePTFE inner layer, the PTFE outer layer, or both. For example, in someinstances FEP layers may be used to increase the material strength ofthe cover. Again, as discussed above, the tie layer may also beconfigured as a portion of the construct configured to be impervious totissue ingrowth or migration.

Further, one or more layers of electrospun PTFE may be used inconnection with a scaffolding structure other than that shown herein. Inother words, the disclosure above relating to covers, layers, tielayers, and related components is applicable to any type of scaffoldingstructure as well as to stents or grafts with no separate scaffoldingstructure at all.

FIGS. 4A-4E illustrate certain steps in a process of manufacturing amultilayer construct for use in connection with a medical appliance.More specifically, these Figures illustrate a process of creating astent covered with electrospun material. Again, this disclosure isequally relevant to all medical appliances that may comprise a cover ormultilayered construct, including grafts, patches, stents, and so on.Additionally, as suggested in the additional examples disclosed below,the illustrated steps may be optional in some instances or augmented byadditional steps in others.

FIG. 4A illustrates a covering inner layer 425 disposed around a mandrel416. As described above, the inner layer 425 may be electrospun directlyonto the mandrel 416, including instances wherein the mandrel 416 wasrotating during the process. In the illustrated embodiment, the innerlayer 425 was electrospun onto a rotating mandrel 416 such that theresultant tube of material has no seam. After the inner layer 425 iselectrospun onto the mandrel 416, the inner layer 425 may then besintered. In the case of PTFE, the membrane may be sintered attemperatures of about 385 degrees C., including temperatures from about360 degrees C. to about 400 degrees C. Sintering may tend to set thestructure of the PTFE, meaning sintering reduces the softness orflowability of the PTFE. Furthermore, as discussed above, sintering orotherwise heat treating the mat may evaporate any water or PEO mixedwith the PTFE, resulting in a material comprised substantially of purePTFE.

Once the inner layer 425 is sintered, the tube of material may beremoved from the mandrel 416, as illustrated in FIG. 4B. As shown in theillustrated embodiment, the inner layer 425 may be “peeled” from themandrel 416 to initially break any adherence of the inner layer 425 tothe mandrel 416. The inner layer 425 may also be removed by pushing thecovering with respect to the mandrel 416, causing the material to bunchas it is removed from the mandrel 416. In some embodiments, low frictioncoatings may alternatively or additionally be applied to the mandrel 416before the inner layer 425 is electrospun. The inner layer 425 may thenbe reapplied to the mandrel 416 by slipping the inner layer 425 over themandrel 416, as illustrated in FIG. 4C.

Once the inner layer 425 is reapplied to the mandrel 416, a wirescaffolding 420 can be formed over the mandrel 416 and the inner layer425, as shown in FIG. 4D. FIG. 4E illustrates an outer layer 430 ofmaterial that may then be electrospun onto the scaffolding 420 and theinner layer 425. The entire construct may then be sintered. Additionallayers may also be added through similar processes.

Many variations to the above-described process are within the scope ofthe present disclosure. For example, one or more layers may be appliedby wrapping strips or mats of material around the mandrel 416 and/or theother layers. Further, some of the layers may be applied by spray or dipcoating the mandrel 416 and/or the other layers. It is within the scopeof this disclosure to vary the process above to apply to any of thelayers, or any additional layers, using any method disclosed herein.

In another example, a stent may be comprised of an inner layer ofelectrospun PTFE, a tie layer of FEP, and an outer layer of PTFE. Theproperties of each of these layers, including percent porosity, matthickness, fiber diameter, and/or average pore size, may be controlledto form a covering layer that inhibits the growth of tissue into orthrough a particular layer or that permits endothelial growth orattachment on a particular layer.

In some such embodiments, the inner layer of PTFE may be electrospun ona mandrel, sintered, removed from the mandrel, and replaced on themandrel and then a scaffolding structure applied around the inner layer(analogous to the procedure illustrated in FIGS. 4A-4D). The FEP tielayer may then be applied by dipping, spraying, applying a film layer,electrospinning, rotational spinning, extrusion, or other processing.

In some embodiments, the FEP layer may be heated such that the FEPbecomes soft, in some cases flowing into open spaces in adjacent PTFElayers. This may tie the FEP layer to adjacent PTFE layers. In someinstances, heating the construct to about 325 degrees C. may allow theFEP to partially flow into openings in adjacent PTFE layers, without theFEP completely flowing through the PTFE mat.

In another particular example, an inner layer of PTFE may be electrospunon a mandrel, sintered, removed, and replaced, and then a scaffoldingstructure applied around the inner layer. An FEP tie layer may then beapplied as a film layer. In some instances this tie layer may be“tacked” into place, for example, by a soldering iron. A tube of PTFE(which may be formed separately by electrospinning onto a mandrel andsintering) may then be disposed over the FEP film layer. The entireconstruct may then be pressured, for example, by applying a compressionwrap. In some embodiments this wrap may comprise any suitable material,including a PTFE-based material. In other embodiments a Kapton film maybe wrapped around the construct before the compression wrap, to preventthe construct from adhering to the compression wrap.

The compressed layers may then be heated above the melting temperatureof the FEP tie layer, but below the sintering temperature of the PTFE.For example, the melt temperature of the FEP may be from about 264degrees C. to about 380 degrees C., including about 325 degrees C. PTFEmay be sintered at temperatures from about 360 degrees C. to about 400degrees C. Thus, the entire construct may be heated to an appropriatetemperature such as about 325 degrees C. In some embodiments theconstruct may be held at this temperature for about 15 to about 20minutes. Heating the FEP layer to about 325 degrees C. may allow the FEPlayer to remain substantially impervious to tissue ingrowth and/orattachment, creating a “barrier” layer within the construct, while stilladhering the FEP to adjacent layers of PTFE. In other embodiments,heating the construct to higher temperatures, such as about 350 degreesC. or more, may be configured to allow the FEP to flow around the PTFEsuch that the entire construct has a higher degree of porosity and theFEP layer is not as impervious to ingrowth.

The joining of the FEP tie layer to the PTFE outer and inner coverlayers may increase the strength of the finished covering. The constructmay then be cooled and the compression wrap and the Kapton filmdiscarded. The construct may then be removed from the mandrel.

A stent formed by the exemplary process described above may beconfigured with desired characteristics of porosity and strength. Insome instances the FEP material may coat the PTFE nanofibers but stillallow for sufficient porosity to permit tissue ingrowth and/orendothelial attachment or growth. The degree to which the FEP coats thePTFE may be controlled by the temperature and time of processing. Thelower the temperature and/or the shorter the time the construct is heldat a certain temperature, the less the FEP may flow. In some instances atie layer of FEP that is impervious to tissue ingrowth into or throughthe layer may be formed by heating the construction only to about 270degrees C.

FIG. 5 illustrates a stent 502 that comprises a scaffolding structure520 and a covering 524. The covering 524 may be comprised of anycombination of layers disclosed herein. Additionally, the stent 502 ofFIG. 5 includes a cuff 540 at both ends of the stent 502. In otherembodiments a cuff 540 may be located at only one end of the stent 502.

The cuff 540 may comprise an additional covering layer on the outsidediameter of the stent 502, disposed adjacent to one or both ends of thestent 502. The cuff 540 may be configured to promote tissue ingrowth,attachment, and/or incorporation into the cuff 540; for example, thecuff 540 may be more porous than an outer layer of the covering 524 ofthe stent 502. Factors such as porosity, type of covering or coating,type of material, use of organic material, and/or use of compositematerials formed of synthetic material and organic material may be usedto create a cuff 540 configured for tissue ingrowth. Again, the cuff 540may be configured to promote tissue ingrowth and/or the growth orattachment of endothelial cells at one or both ends of the stent 502.When implanted in the body, the cuffs 540 may tend to “anchor” the endsof the stent 502 with respect to the vessel walls, reducing the relativemovement of the stent ends with respect to the vessel walls. Such areduction in movement may lessen irritation of the vessel by the stentends, minimizing complications such as edge stenosis. Cuffs 540 may beconfigured for use in CV type applications in some instances.Furthermore, a band of porous material analogous to the cuff 540illustrated may be coupled to any medical appliance to anchor a portionof such a device.

In some embodiments, the outer layer of the covering 524 of the stent502 may be relatively non-porous to inhibit tissue ingrowth into orthrough the outer layer, but the cuff 540, disposed about the outerlayer, may provide a section near each end at which some tissueingrowth, attachment, or incorporation may occur.

The cuff 540 may be comprised of an electrospun material, such as PTFE,and may be bonded to the outer covering layer through any method,including methods of multilayer device construction described herein.For example, a layer of FEP may be disposed between the outer coveringlayer and the cuff 540, and heated to bond the layers. In otherembodiments the cuff 540 may comprise a collagen layer that is coupledto the stent. Further, a co-electrospun collagen and PTFE cuff 540 maybe utilized.

The current disclosure relates to medical appliances, including stents,which may comprise a frame structure provided in connection with one ormore coverings or coatings. It will be appreciated that, thoughparticular structures, coverings, and coatings are described herein, anyfeature of the frames or coverings and/or coatings described herein maybe combined with any other disclosed feature without departing from thescope of the current disclosure. For example, certain Figures referencedbelow show a metal frame without any covering or coating; the featuresdescribed and illustrated in those Figures may be combined with anycombination of coverings or coatings disclosed herein. Further, as usedherein, the term “frame” refers to a support structure for use inconnection with a medical appliance. For instance, a scaffoldingstructure, such as that described in connection with FIGS. 4A-4E, above,is an example of a frame used in connection with a medical appliance. Insome embodiments, a medical appliance—such as a stent—may comprise aframe alone, with no covering, coating, or other components.

Moreover, the current disclosure is applicable to a wide variety ofmedical appliances that may utilize any of the electrospun matsdisclosed herein, including medical appliances that comprise multiplelayers. For example, a hernia patch may comprise a two-layeredconstruction, with one side of the patch configured to allow tissueingrowth and/or attachment (for bonding and healing) and the other sideconfigured to resist such ingrowth and/or attachment (to make the secondside “slippery” with respect to surrounding tissue). Further, a patch asdescribed above may also comprise a tie layer disposed between the twoexterior layers. The tie layer may be configured to resist tissueingrowth or attachment into or through the patch and/or to providemechanical properties such as strength to the construct.

FIGS. 6, 7A, and 7B show views of a possible embodiment of a frame foruse in connection with a medical appliance such as a stent or graft.FIG. 7C is an alternative configuration of a portion of the framestructure. FIGS. 8 and 9 are views of one embodiment of a frame thatincludes flared ends. FIG. 10 illustrates one embodiment of how a wiremay be shaped to form a frame.

Frames for use in connection with medical appliances may be fabricatedor formed into particular geometries through a variety of means. Forexample, a frame may be cut from a single tube of material, includingembodiments wherein the frame is first laser cut, then expanded. Inother embodiments, the frame may be molded, including embodimentswherein the frame is molded from a polymeric material. In still otherembodiments, powder metallurgical processes, such as powderedcompression molding or direct metal laser sintering, may be used.

FIG. 6 illustrates a front elevation view of an embodiment of a frame.The illustrated embodiment depicts one embodiment of a configuration fora metal wire 650 forming a frame. As depicted in FIG. 6, the frame mayconsist of a single continuous wire.

Referring generally to FIGS. 6, 7A, and 7B, particular features of theillustrated frame structure are indicated. It will be appreciated thatthe numerals and designations used in any figure apply to analogousfeatures in other illustrated embodiments, whether or not the feature isso identified in each figure. As generally shown in these Figures, theframe structure may consist of a wire 650 shaped to form the frame. Thewire 650 may be shaped in a wave-type configuration, the waves definingapexes 652 and arms 654 of the frame structure. The frame may further becoupled to a covering layer (not pictured). Additionally, in someembodiments, any covering as disclosed herein may be applied to any typeof frame, for example, laser cut frames, polymeric frames, wire frames,and so forth.

The frame may be designed such that the midsection is “harder” than theends. The “hardness” of the frame refers to the relative strength of thestructure (e.g., its compressibility). A harder portion of the framewill have greater strength (i.e., exert a greater radial outward force)than a softer portion. In one embodiment, the midsection is harder thanthe proximal and distal end sections, which are relatively softer.Further, a frame may be configured to be flexible to facilitate theability of the device to conform to the native anatomy at which thedevice is configured for use. Similarly, covered devices may beconfigured with covers that conform to the native anatomy at a therapysite.

Additionally, the frame may be configured to allow the entire device tobe crimped into a relatively low-profile configuration for delivery. Forexample, devices of a certain diameter or constrained profile are morefeasible for delivery at certain vascular or other access points thanothers. For example, in many instances a device configured for insertionvia the radial artery may be relatively smaller than devices configuredfor insertion via the generally larger femoral artery. A frame may beconfigured to be crimped into a particular profile to enable potentialaccess at various or desired access points. Similarly, devices having noframe may be configured to be disposed in a particular profile tofacilitate access and delivery. Once a device is positioned within thebody it may be expanded or deployed in a number of ways, including useof self-expanding materials and configurations. Additionally, someconfigurations may be designed for expansion by a secondary device, suchas a balloon.

Four basic design parameters may be manipulated to influence theproperties (hardness, strength, crush force, hoop force, flexibility,etc.) of the illustrated frame. These properties are (1) apex to apexdistance, designated as H_(x) in FIGS. 6 and 7A; (2) arm length,designated as A_(x) in FIGS. 6 and 7A; (3) apex radius, designated asR_(x) in FIG. 7A; and (4) the diameter of the wire 650. These values mayor may not be constant at different points on a frame. Thus, thesubscript “x” is used generically; that is, each distance identified as“H” refers to an apex to apex distance with subscripts 1, 2, 3, etc.,signifying the apex to apex distance at a particular point. It will beappreciated that these subscript designations do not necessarily referto a specific distance, but may be used relatively (i.e., H₁ may bedesignated as smaller than H₂ without assigning any precise value toeither measurement). Further, as will be apparent to one skilled in theart having the benefit of this disclosure, an analogous pattern ofmeasurements and subscripts is employed for other parameters describedherein, for example A_(x) and R_(x).

The overall frame design may be configured to optimize desired radialforce, crush profile, and strain profile. The frame design parametersmay each be configured and tuned to create desired characteristics. Forexample, the strain profile may be configured to be less than thefailure point for the material being used.

A first parameter, the apex to apex distance, is designated as H. Thismeasurement signifies the distance between a first apex and a secondapex where both apexes substantially lie along a line on the outsidediameter of the frame that is co-planar with, and parallel to, thelongitudinal axis of the frame. In some embodiments, H_(x) may beconstant along the entire length of the frame. In other embodiments thelength of the frame may be divided into one or more “zones” where H_(x)is constant within a zone, but each zone may have a different H. Instill other embodiments H_(x) may vary along the entire length of theframe. H_(x) may be configured, in connection with the other designparameters, to determine the properties of the frame. Generally, regionsof the frame with a smaller H_(x) value will be harder than regions witha larger H_(x) value.

In the embodiment illustrated in FIG. 6, there are two “flare zones” ateither end of the frame and a midbody zone along the remaining length ofthe frame. In the illustrated embodiment, H₁ designates the apex to apexdistance in the midbody zone of the frame and H₂ designates the apex toapex distance in the flare zones of the frame. In the illustratedembodiment, the apex to apex distance, H₂, is the same in both the flarezone near the distal end of the frame and the flare zone near theproximal end of the frame. In some embodiments H₁ may be smaller thanH₂, resulting in a frame that is relatively harder in the midbody andrelatively softer on the ends. A frame with such properties may beutilized in applications where strength is necessary along the midbody,for example to treat a tumor or other occlusion, but the ends areconfigured to rest on healthy tissue where softer ends will minimizetrauma to the healthy tissue.

In embodiments where soft ends and a hard midbody are desirable, H₁ maybe between about 2 mm and 30 mm, and H₂ between about 2.1 mm and 30.1mm. For example, in frames configured for use in connection with stentsfor CV or PV applications, H₁ may be between about 3 mm and 10 mm, andH₂ between about 3.1 mm and 10.1 mm, such as 3 mm<H₁<8 mm and 3.5mm<H₂<9 mm, 3 mm<H₁<6.5 mm and 4 mm<H₂<8 mm, or 3 mm<H₁<5 mm and 5.5mm<H₂<6.5 mm.

In other embodiments where two or more apex to apex lengths are presentin one frame, the change in apex to apex length may be correlated to thedisplacement of the apexes from the midpoint of the frame. In otherwords, the apex to apex length may increase incrementally as one movesaway from the midpoint of the frame toward the ends in a manner thatgives the frame the same geometry, and therefore the same properties, oneither side of the midpoint of the length of the frame. In otherembodiments, different geometries may be utilized at any point along thelength of the frame. It will be appreciated that the ranges of valuesfor H_(x) disclosed above apply analogously to embodiments where theframe has multiple apex to apex lengths. For example, in one embodimenta frame may have an apex to apex length at midbody within one of theranges disclosed above for H₁, and the value of H_(x) may varyincrementally, in steps, or some other pattern, along the length of theframe, reaching an apex to apex length at the ends within thecomplementary range for H₂.

Moreover, in some embodiments, the value of H_(x) may be small enoughthat adjacent coils are “nested” within each other. In other words, theapexes of a first helical coil may extend up into the spaces just belowthe apexes of the next adjacent coil. In other words, apexes of lowercoils may extend a sufficient amount so as to be disposed between thearms of higher coils. In other embodiments the value of H_(x) may belarge enough that adjacent coils are completely separated. Inembodiments wherein adjacent coils are “nested,” the number of wires atany particular cross-section of the stent may be higher than anon-nested stent. In other words, cutting the frame along an imaginaryplane disposed orthogonally to the longitudinal axis of the frame willintersect more wires if the frame is nested as compared to not nested.The smaller the value of H_(x), the more the rows may be intersected bysuch a plane (that is, more than just the next adjacent row may extendinto the spaces below the apexes of a particular row). Nested frames maycreate relatively higher strains in the frame when a stent comprised ofthe frame is loaded into a delivery catheter. In some instances thedelivery catheter for a nested frame may therefore be relatively largerthan a delivery catheter configured for a non-nested frame. Further,nested frames may be relatively stiff as compared to non-nested stentswith similar parameters.

As will be apparent to those skilled in the art having the benefit ofthis disclosure, frames with a hard midbody and soft ends may bedesirable for a variety of applications. Further, in some instances abasically “symmetric” frame may be desirable; in other words, a framewith certain properties at the midbody section and other properties atthe ends, where the properties at both ends are substantially identical.Of course, other embodiments may have varied properties along the entirelength of the frame. It will be appreciated that while the effect ofchanging variables, for instance the difference between H₁ and H₂, maybe described in connection with a substantially symmetric stent (as inFIG. 6), the same principles may be utilized to control the propertiesof a frame where the geometry varies along the entire length of theframe. As will be appreciated by those skilled in the art having thebenefit of this disclosure, this applies to each of the variableparameters described herein, for example H_(x), A_(x), and R_(x).

A second parameter, arm length, is designated as A_(x) in FIGS. 6 and7A. As with H_(x), A_(x) may be constant along the length of the frame,be constant within zones, or vary along the length of the frame.Variations in the length of A_(x) may be configured in conjunction withvariations in the other parameters to create a frame with a particularset of properties. Generally, regions of the frame where A_(x) isrelatively shorter will be harder than regions where A_(x) is longer.

In some embodiments, the arm length A₁ near the midsection of the framewill be shorter than the arm length A₂ near the ends. This configurationmay result in the frame being relatively harder in the midsection. Inembodiments where soft ends and a hard midbody are desirable, A₁ may bebetween about 2 mm and 30 mm, and A₂ between about 2.1 mm and 30.1 mm.For example, in frames for CV or PV applications, A₁ may be betweenabout 2 mm and 10 mm, and A₂ between about 2.1 mm and 10.1 mm, such as2.5 mm<A₁<8 mm and 3 mm<A₂<9 mm, 3 mm<<6 mm and 4 mm<A₂<7.5 mm, or 4mm<<5 mm and 5 mm<A₂<6 mm.

In other embodiments where two or more arm lengths are present in oneframe, the change in arm length may be correlated to the displacement ofthe arm from the midpoint along the frame. In other words, the armlength may increase incrementally as one moves away from the midpoint ofthe frame toward the ends in a manner that gives the frame the samegeometry, and therefore the same properties, on either side of themidpoint of the length of the frame. In other embodiments, differentgeometries may be utilized at any point along the length of the frame.It will be appreciated that the ranges of values for A_(x) disclosedabove apply analogously to embodiments where the frame has multiple armlengths. For example, in one embodiment a frame may have an arm lengthat midbody within one of the ranges disclosed above for A₁, and thevalue of A_(x) may vary incrementally, in steps or some other pattern,along the length of the frame reaching an arm length at the ends withinthe complementary range for A₂.

A third parameter, the apex radius, is designated as R₁ in FIG. 7A. Aswith H_(x), and A_(x), R_(x) may be configured in order to createdesired properties in a frame. In some embodiments, the inside radius ofeach apex may form an arc that has a substantially constant radius. Asshown by a dashed line in FIG. 7A, this arc can be extended to form acircle within the apex. The measurement R_(x) refers to the radius ofthe arc and circle so described. Further, in some embodiments the armsand apexes of the frame are formed by molding a wire around pinsprotruding from a mandrel. The radius of the pin used gives the apex itsshape and therefore has substantially the same radius as the apex. Insome embodiments R_(x) will be constant along the entire length of theframe, be constant within zones along the length of the frame, or varyalong the entire length of the frame. Variations in the magnitude ofR_(x) may be configured in conjunction with variations in the otherparameters to create a frame with a particular set of properties.Generally, regions of the frame where R_(x) is relatively smaller willbe harder than regions where R_(x) is larger.

Furthermore, in some instances, smaller values of R_(x) may result inrelatively lower strain in the wire frame when the frame is compressed,for example when the frame is disposed within a delivery catheter.Moreover, wires of relatively larger diameters may result in relativelylower strain at or adjacent to the radius measured by R_(x) whencompressed, as compared to wires of smaller diameters. Thus, in someinstances, the strain may be optimized for a particular design byvarying the value of R_(x) and the diameter of the wire forming theframe.

Like the other variables, R_(x) may take on a range of values dependingon the application and the desired properties of the frame. In someembodiments R_(x) may be between about 0.12 mm and 1.5 mm, includingfrom about 0.12 to about 0.64 mm. For example, in frames configured foruse with stents for CV or PV applications, R_(x) may be between about0.35 mm and 0.70 mm, such as 0.35 mm<R_(x)<0.65 mm, 0.35 mm<R_(x)<0.6mm, or 0.4 mm<R_(x)<0.5 mm.

It will be appreciated that the disclosed ranges for R_(x) apply whetherthe value of R_(x) is constant along the length of the frame, whetherthe frame is divided into zones with different R_(x) values, or whetherR_(x) varies along the entire length of the frame.

The fourth parameter, wire diameter, is discussed in detail inconnection with FIG. 10 below.

FIG. 7A illustrates a cutaway view of the front portions of two adjacentcoils of a frame. The portions of the coils depicted are meant to beillustrative, providing a clear view of the three parameters H_(x),A_(x), and R_(x). It will be appreciated that all three of theseparameters may be configured in order to create a frame with particularproperties. Any combination of the values, ranges, or relativemagnitudes of these parameters disclosed herein may be used within thescope of this disclosure. As an example of these values taken together,in one embodiment of a CV or PV frame with a relatively hard midbody andsofter ends, H₁ may be about 4 mm and H₂ about 5.9 mm, A₁ may be about4.5 mm and A₂ about 5.6 mm, and R₁ about 0.5 mm.

FIG. 7B is a close-up view of one end of a frame. In embodiments wherethe frame is formed by a single continuous wire, FIG. 7B illustrates oneway in which the end 656 of the wire may be coupled to the frame. Asillustrated, the wire may be disposed such that the final coilapproaches and runs substantially parallel to the previous coil. Thisconfiguration results in the apex to apex distance between the two coilsdecreasing near the end 656 of the wire. In some embodiments thistransition will occur along the distance of about 4 to 8 apexes alongthe length of the wire. For example, if a frame is configured with anapex to apex spacing of H₂′ along the region of the frame nearest to theends, the apex to apex distance will decrease from H₂′ to a smallerdistance that allows the end 656 of the wire to meet the prior coil (asillustrated in FIG. 7B) over the course of about 4 to 8 apexes.

FIG. 7C illustrates an alternative configuration of a portion of aframe. In the embodiment of FIG. 7C, apexes 652′ alternate in relativeheight along the length of the wire. In particular, in the embodimentshown, the apexes form a pattern comprising a higher apex, a shorterapex, a higher apex, a shorter apex, and so on, around the helical coil.In some instances, a frame may be configured with alternating apexes atone or both ends of the frame. For example, a frame as shown in FIG. 6may be configured with the pattern of apexes 652′ and arms 654′ shown inFIG. 7C at one or both ends of the frame. Such an alternating pattern ofapexes may distribute the force along the vessel wall at the ends of theframe, thus creating relatively a-traumatic ends.

The end 656 may be attached to the frame in a variety of ways known inthe art. The end 656 may be laser welded to the frame or mechanicallycrimped to the frame. In embodiments where the frame is an element of amedical appliance further comprising a polymer cover, the end 656 may besecured by simply being bound to the cover. In other instances, a stringmay be used to bind or tie the end 656 to adjacent portions of theframe. Similarly, in some instances, a radiopaque marker may be crimpedaround the end 656 in such a manner as to couple the end 656 to theframe. Additionally, other methods known in the art may be utilized.

Furthermore, in some embodiments the frame may be configured withradiopaque markers at one or more points along the frame. Such markersmay be crimped to the frame. In other embodiments a radiopaque ribbon,for example a gold ribbon, may be threaded or applied to the frame. Insome embodiments these markers may be located at or adjacent to one orboth ends of the frame. Any radiopaque material may be used, for examplegold, bismuth, or tantalum. Radiopaque elements may be configured tofacilitate the delivery and placement of a device and/or to facilitateviewing of the device under fluoroscopy.

Referring again to FIG. 6 as well as to FIGS. 8 and 9, the frame may beconfigured with flared ends. It will be appreciated that in certainembodiments a frame may have a flare at both the proximal and distalends, only at the proximal end, only at the distal end, or at neitherend. In certain of these embodiments the frame may have a substantiallyconstant diameter in the midbody zone of the frame, with the endsflaring outward to a larger diameter. It will be appreciated that thegeometry of the flares at the proximal and distal ends may or may not bethe same.

In the embodiment illustrated in FIG. 6, the frame has a diameter, D₁,at the midbody of the frame. This diameter may be constant along theentire midbody of the frame. The illustrated embodiment has a seconddiameter, D₂, at the ends. This change in diameter creates a “flarezone” at the end of the frame, or an area in which the diameter isincreasing and the frame therefore may be described as including a“flared” portion. In some embodiments the flare zone will be from about1 mm to 60 mm in length. For example, in certain frames configured foruse with stents designed for CV or PV applications, the flare zone maybe from about 3 mm to about 25 mm in length, such as from about 4 mm toabout 15 mm or from about 5 mm to about 10 mm in length.

The diameter of the stent at the midbody, the diameter at one or bothflares, or all of these dimensions may be configured to be slightlylarger than the body lumen in which the device is configured for use.Thus, the size of the device may cause interference with the lumen andreduce the likelihood the device will migrate within the lumen. Further,active anti-migration or fixation elements such as barbs or anchors mayalso be used.

FIGS. 8 and 9 also illustrate how a frame may be flared at the ends.Diameters D₁′ and D₁″ refer to midbody diameters, analogous to D₁, whileD₂′ and D₂″ refer to end diameters analogous to D₂. Further, asillustrated in FIG. 9, the flared end may create an angle, alpha,between the surface of the frame at the midbody and the surface of theflare. In some instances the flare section will uniformly flare out at aconstant angle, as illustrated in FIG. 9. In some embodiments anglealpha will be from about 1 degree to about 30 degrees. For example, insome frames configured for use with stents designed for CV or PVapplications, alpha will be from about 2 degrees to about 8 degrees,such as from about 2.5 degrees to about 7 degrees or from about 3degrees to about 5 degrees. In one exemplary embodiment, alpha may beabout 3.6 degrees.

The frame of FIG. 6 also has a length L. It will be appreciated thatthis length can vary depending on the desired application of the frame.In embodiments where the frame has flare zones at the ends, longerframes may or may not have proportionally longer flare zones. In someembodiments, this flare zone may be any length described above,regardless of the overall length of the frame.

The disclosed frame may be formed in a variety of sizes. In someembodiments, L may be from about 10 mm to about 200 mm. For example, inCV applications the frame may have a length, L, of from about 40 mm to100 mm or any value between, for example, at least about 50 mm, 60 mm,70 mm, 80 mm, or 90 mm. In PV applications the frame may have a length,L, of from about 25 mm to 150 mm or any value between, for example, atleast about 50 mm, 75 mm, 100 mm, or 125 mm. The frame may also belonger or shorter than these exemplary values in other applications.

Likewise the frame may be formed with a variety of diameters. In someembodiments the midbody diameter of the frame may be from about 1 mm toabout 45 mm, including from about 4 mm to about 40 mm. For example, inCV or PV applications the frame may have a midbody inside diameter ofabout 3 mm to 16 mm, or any distance within this range such as betweenabout 5 mm and about 14 mm or between about 7 mm and about 10 mm.Moreover, in some instances, the diameter, or a diameter-likemeasurement of the frame, may be described as a function of othercomponents. For example, the frame may be configured with a particularnumber of apexes around a circumference of the frame. For example, someframes may be configured with between about 2 and about 30 apexes arounda circumference of the frame.

The frame may or may not be configured with flared ends regardless ofthe midbody diameter employed. In some CV embodiments the maximumdiameter at the flared end will be between about 0.5 mm and about 2.5 mmgreater than the midbody diameter. For example, the maximum diameter atthe flared end may be between about 1 mm and about 2 mm, oralternatively between about 1.25 mm and about 1.5 mm, such as about 1.25mm or about 1.5 mm greater than the midbody diameter.

Referring now to FIG. 10, the frame may be formed from a singlecontinuous wire. In some embodiments the wire may be comprised ofNitinol (ASTM F2063) or other suitable materials. In some embodimentsthe wire will have a diameter between about 0.001 inch and about 0.05inch, including from about 0.005 inch and about 0.025 inch. For example,in some frames designed for CV or PV applications, the wire diameter maybe from about 0.008 inch to about 0.012 inch in diameter includingcertain embodiments where the wire is from about 0.009 inch to about0.011 inch in diameter or embodiments where the wire is about 0.010 inchin diameter. Furthermore, frames configured for the thoracic aorta maybe formed of wires up to 0.020 inch in diameter, including wires betweenabout 0.010 inch and 0.018 inch in diameter.

FIG. 10 illustrates how, in some embodiments, the wire 650 may be woundin a helical pattern creating coils that incline along the length of thestent. The waves of the wire that form the arms and apexes may becentered around this helix, represented by the dashed line 660.

In some embodiments, a stent, graft, or other tubular device maycomprise a tapered segment along the length of the device. A taper maybe configured to reduce the velocity of fluid flow within the device asthe fluid transitions from a smaller diameter portion of the device to alarger diameter portion of the device. Reducing the fluid velocity maybe configured to promote laminar flow, including instances wherein atubular member is tapered to promote laminar flow at the downstream endof the device.

Further, in some embodiments, a stent or other tubular member may bepositioned at a junction between two or more body lumens. For example,FIG. 11A illustrates a stent 702 a disposed at an intersection betweentwo body lumens. In some embodiments, stent 702 a may be configured topromote laminar flow at the intersection of the lumens.

FIG. 11B illustrates a portion of a stent 702 b having a tapered segment705 b which may be configured to reduce flow velocity within the stent702 b. In some embodiments, such as that of FIG. 11B, the taperedsegment 705 b may be positioned upstream of the downstream end of thestent 702 b. FIG. 11C illustrates another exemplary embodiment of aportion of a stent 702 c having a tapered segment 705 c adjacent thedownstream end of the stent 702 c. Either tapered segment (705 b, 705 c)may be used in connection with any stent, including embodiments whereinthe tapered segment is configured to promote laminar flow in and aroundthe stent. For example, the stent 702 a of FIG. 11A may be configuredwith either tapered portion (705 b, 705 c) to promote laminar flow outof the stent 702 a and at the junction between the body lumens of FIG.11A.

Use of electrospun coatings may facilitate application of a covering ofuniform thickness along a tapered stent. For example, in someembodiments, electrospun coatings may be configured to evenly coatdevices comprised of various geometries. An electrospun coating maydeposit a substantially even coating along various geometries such astapers, shoulders, and so forth.

Additionally, various additional processing steps, methods, procedures,and systems for serially deposited fiber mats, such as electrospun orrotational spun mats, are within the scope of this disclosure. Materialscomprising serially deposited fiber mats which have been processed byany of the methods or systems described below are likewise within thescope of this disclosure. These processes and materials may be used tocreate multilayered constructs having one or more layers of seriallydeposited fiber material which has been post processed as describedbelow and/or having one or more layers of serially deposited fibermaterial which has not been post processed. The post processing methodsand related materials described below describe various methods ofmodifying the material properties of serially deposited fiber layers to,for example, change the strength of the material, change the surfacecharacteristics of the material, change the porosity of the material,set the material in a particular geometry or shape, and so forth.

Serially deposited fiber mats may comprise a membrane in the form of asheet, a sphere, a strip, or any other geometry. As used herein, theterm “membrane” refers to any structure comprising serially depositedfibers having a thickness which is smaller than at least one otherdimension of the membrane. Examples of membranes include, but are notlimited to, serially deposited fiber mats or lattices forming sheets,strips, tubes, spheres, covers, layers, and so forth. Additionally, anymaterial which can be serially deposited as fibers may be processed asdescribed below.

Further, as used herein, references to heating a material “at” aparticular temperature indicate that the material has been disposedwithin an environment which is at the target temperature. For example,placement of a material sample in an oven, the interior of the ovenbeing set at a particular temperature, would constitute heating thematerial at that particular temperature. While disposed in a heatedenvironment, the material may, but does not necessarily, reach thetemperature of the environment. The term “about,” as used herein inconnection with temperature, is meant to indicate a range of ±5 degreesC. around the given value. The term “about” used in connection withquantities or values indicates a range of ±5% around the value.

Serially deposited membranes may be processed to alter the strength orother characteristics of the material by stretching the membrane in oneor more directions. In some embodiments the membrane may initially besintered after it is serially deposited. The membrane may then be heatedat a particular temperature prior to further processing of the membrane.As further outlined below, heating and stretching a membrane of seriallydeposited fibers may tend to cause increased strength in the directionthe membrane is stretched. In some embodiments, the material may alsoexhibit increased fiber alignment in the direction of stretching.

Temperatures at which materials may be heated prior to processing mayvary depending on the material and depending on the desiredcharacteristics of the material after processing. For example, apolymeric membrane may show more or less fiber alignment afterprocessing depending on various factors, such as the temperature atwhich the materials are heated. In some instances a membrane may beheated at a temperature at or above the crystalline melt point of thematerial comprising the membrane, though it is not necessary to heat thematerial as high as the crystalline melt temperature to stretch processthe material.

In the case of polymeric materials which are sintered, the step ofheating the membrane may be performed as a separate and distinct stepfrom sintering the membrane, or may be done as the same step. Forexample, it is within the scope of this disclosure to process a membranedirectly after sintering the membrane, while the membrane is at anelevated temperature due to the sintering process. It is likewise withinthe scope of this disclosure to obtain a previously sintered membranewhich may have been previously cooled to ambient or room temperature,then heat the membrane as part of a heating and stretching process.

Membranes or any other mat or lattice of serially deposited fibers maybe stretched in any direction as part of a heating and stretchingprocess. For example, a tubular membrane may be stretched in theaxial/longitudinal direction, the radial direction, or any otherdirection. Further, it is within the scope of this disclosure to stretcha membrane in multiple directions, either simultaneously or as part ofseparate steps. For example, a tubular membrane may be stretched bothaxially and radially after the membrane is initially heated, or themembrane may be stretched in these or other directions as part ofdistinct and separate steps. Additionally, the membrane may be heatedmultiple times during such a process.

Various methods, modes, mechanisms, and processes may be utilized toapply forces to stretch materials. For example, force may be appliedthrough mechanical, fluidic, electro-magnetic, gravitational, and/orother mechanism or modes. In embodiments wherein force is appliedthrough fluidic interaction, a pressurized gas or liquid could be usedto generate the force while the material is at an elevated temperature.The fluid may be stagnant or recirculating. Further, the fluid may beused to heat and/or cool the material. For example, the liquid may beused to rapidly cool the material, locking the microstructure andgeometry.

A heated and stretched membrane may be held in a stretched positionwhile the membrane cools. For example, a membrane may be heated at anelevated temperature prior to stretching, stretched while the membraneis at an elevated temperature, then held in the stretched position whilethe membrane cools to an ambient temperature, such as room temperature.Depending on the process, when the membrane is stretched, it may be at atemperature lower than the temperature at which it was heated, and itmay or may not cool completely to the ambient temperature while theposition is held.

Processing a mat or lattice of serially deposited fibers as by heatingand stretching may alter various material properties of the mat orlattice. For example, and as further outlined below, heating andstretching a fiber mat may increase the durability of the material,increase the smoothness of the material, increase handlingcharacteristics, increase the tensile strength of the material, increaseresistance to creep, or otherwise alter the material. Further, in someembodiments, heating and stretching the material tends to align aportion of the fibers which comprise the mat in the direction thematerial is stretched. This alignment of the microstructure and/ornanostructure of the material may impact microscale and/or nanoscaleinteractions between the mat and other structures, such as body cells.Fiber alignment may likewise alter the flow characteristics of a fluidflowing in contact with the mat. For example, a tubular membraneconfigured to accommodate blood flow may exhibit different flowconditions through the tube if the fibers are aligned by heating andstretching as compared to randomly disposed fibers.

Additionally, heating and stretching a mat may or may not tend to alignthe fibers in the direction the material is stretched. In someembodiments, the degree of fiber alignment may be related to thetemperature at which the mat was heated prior to stretching. Further,stretching a mat in multiple directions may tend to maintain randomfiber disposition of a mat in embodiments wherein the original matexhibited generally random fiber disposition.

Regardless of whether heating and stretching tend to align the fibers inthe direction the mat was stretched, the mat may exhibit differentproperties in a stretched direction as compared to a non-stretcheddirection. For example, the mat may exhibit increased tensile strengthand/or increased resistance to creep in the stretched direction whilethese properties may be generally unchanged or decreased in anon-stretched direction. Further, stretching may increase the porosityof a mat of serially deposited fibers. In some embodiments, stretchingmay increase the porosity of a mat by up to 10 times the originalporosity, including up to eight times, up to six times, up to fourtimes, and up to two times the original porosity. In some embodiments, amat may be stretched while at room temperature to increase porosity, toincrease strength, or to modify other properties of the mat.

Additionally, in some embodiments, a tubular membrane heated andstretched in the axial direction may exhibit greater tensile strength inthe axial direction as compared to the properties of the membrane priorto heating and stretching. In this example, the tensile strength in theradial direction, however, may be similar to the tensile strength of themembrane in that direction prior to heating and stretching. Thus, themembrane may have similar properties in both these directions prior toheating and stretching, but may exhibit greater tensile strength in theaxial direction after heating and stretching. In some embodiments, thetensile strength of the membrane is 150%-300% that of the membrane priorto heating and stretching in the direction of stretching. For example,the tensile strength of the membrane is at least 150%, at least 200%, atleast 250% or at least 300% that of the membrane prior to heating andstretching in the direction of stretching. In some embodiments, a matmay exhibit decreased tensile strength or other changes in properties ina non-stretched direction disposed perpendicular to the direction ofstretching, as compared to those properties prior to stretching.

In some embodiments, a material is stretched in multiple directions toincrease strength or otherwise alter the properties in those directions.In other embodiments, heating and stretching change the properties inonly one direction. For example, a tube may be configured to bebolstered against creep in the radial direction, without substantiallyaffecting the material properties in the axial direction. Again, in someinstances an increase in particular properties in a first direction iscorrelated with a decrease in one or more of the same properties in asecond direction.

Additionally, materials having different properties in differentdirections may be combined to create a composite construct. For example,a composite construct comprising at least one layer of axially stretchedmaterial and at least one layer of radially stretched material mayexhibit increased strength in both directions. Various layers havingvarious properties may be combined to tailor the properties of theresultant construct. It is within the scope of this disclosure to bondadjacent layers through various processes, including use of tie layersdisposed between layers and bonded to each layer, heating adjacentlayers to create fiber entanglement, use of adhesives, and so forth. FEPmay be used as a tie layer in some embodiments. Further, ePTFE may beused as a tie layer in some embodiments. One embodiment of a compositetube can be created by helically or cigar wrapping a tube of seriallydeposited fibers (un-stretched) with a film of heat and stretchprocessed material, creating a porous luminal layer and a strong creepresistant reinforcement layer. Additionally, layers (such as animpervious layer and/or a porous abluminal layer) may be added to theconstruct as well. Each layer may be configured to optimize aphysiologic interaction, for example.

Multilayered constructs may further comprise reinforcing structures,such as metal scaffolds or frames. In some embodiments, a reinforcingstructure may comprise one of: Nitinol, stainless steel, or titanium.Any layer of a construct may be configured to be a blood contactinglayer. Blood contacting layers may be configured to interact with theblood or other biological elements and may be configured with certainflow characteristics at the blood interface. Further, any layer of amultilayered construct may be configured to be impermeable to tissue orfluid migration. For example an impermeable tie layer may be disposedbetween porous inner and outer layers of a construct.

Single layer devices or multilayered constructs within the scope of thisdisclosure may comprise tubes, grafts, stents, stent grafts, vasculargrafts, patches, prosthetics, or any other medical appliance. Medicalappliances configured for oral surgery and/or plastic surgery are alsowithin the scope of this disclosure.

Again, heat and stretch processing may increase strength in thestretched direction while decreasing strength in a directionperpendicular to the stretched direction. For example, a tubularmembrane stretched in the axial direction may exhibit greater strengthin the axial as opposed to the radial direction. Further, a membrane soprocessed may exhibit greater elasticity or “spring” in thenon-stretched direction oriented perpendicular to the stretcheddirection.

Heating and stretching a mat or lattice of serially deposited fibers maytend to decrease the thickness of the mat or lattice. For example, atubular mat stretched in the range from 200% to 450% may exhibit adecrease in material thickness of between 10% and 90%, including from20% to 80% and from 40% to 60%. Embodiments within these ranges may notexhibit holes or defects from the stretching process, and the overallsurface quality of the material may be maintained after stretching.Further, these ranges are intended to correlate the degree of stretchingand the decrease in material thickness, not to constitute upper or lowerbounds. Materials may be stretched further than the given range tofurther decrease the material thickness, for instance.

As stated above, it is within the scope of this disclosure to heat andstretch various serially deposited fiber mats comprising variousmaterials. Many of the examples discussed below refer particularly toPTFE fiber mats which have been processed in a variety of ways. Theseexamples, or any other example referencing PTFE, may analogously applyto other materials as well. Specific temperatures for heating orotherwise processing a material may be analogously applied to othermaterials by considering the material properties (such as melting point)of such materials and analogizing to the examples below.

Generally, serially deposited PTFE fiber mats may be heated attemperatures between about 65 degrees C. and about 400 degrees C. whileheating and stretching the mats. For example, serially deposited PTFEfiber mats may be heated at temperatures above about 65 degrees C.,above about 100 degrees C., above about 150 degrees C., above about 200degrees C., above about 250 degrees C., above about 300 degrees C.,above about 350 degrees C., above about 370 degrees C., and above about385 degrees C. Additionally, serially deposited PTFE fiber mats may bestretched at room temperature (22 degrees C.) without heating.

Serially deposited PTFE mats may be stretched from 150% to 500% of theinitial length of the mat in the direction of stretching, includingstretching mats to between 200% and 350%, between 250% and 300%, andbetween 300% and 500% of the original length of the mats in thedirection of stretching. The amount of length change may be related tothe temperature at which the mat is heated, the force applied when themat is stretched, the original thickness of the mat, and the rate atwhich the mat is stretched.

Processing serially deposited fiber mats or lattices through heating andstretching may impact various properties of the mats. Tensile strength,resistance to creep, elasticity, and so forth may all be impacted. Insome embodiments, processed mats are used as layers of multilayeredconstructs to provide particular properties in a particular direction.

The temperature at which mats of serially deposited PTFE fibers areheated may affect the tendency of the fibers of the mats to align afterthe mats are stretched. Higher temperatures generally correlate withincreased fiber alignment. Generally, PTFE mats heated at or above 370degrees C. exhibit more fiber alignment than mats heated at temperatureslower than 370 degrees C. Additionally, an increase in tensile strengthis correlated with heating and stretching PTFE, whether or not the matwas heated at 370 degrees C. or more. The amount of the increase intensile strength may be affected by the temperature at which the mat washeated and the amount the material was stretched.

Serially deposited fibers may be set in various geometries byconstraining the fibers in a particular geometry and heating the fibers.For example, in some embodiments, constraining a previously sintered (orotherwise structurally set) mat or lattice of serially deposited fibersin a particular configuration, softening the material of the mat orlattice (for example by heating), and allowing the material to reset mayresult in a “memory” effect wherein the material retains at least aportion of the constrained geometry. Materials may be shape-set asdescribed herein whether or not the materials have been heated andstretched as described above.

In embodiments comprising serially deposited polymeric fibers, heatingthe material at about the crystalline melt point of the material mayfacilitate setting of the geometry.

In one exemplary embodiment, a tubular membrane may be seriallydeposited on a mandrel, sintered, and removed from the mandrel. Thoughthis specific example includes a tubular membrane, the presentdisclosure also applies to sheets, spheres, and other geometries ofserially deposited fiber mats. The tubular membrane of sintered seriallydisposed polymeric fibers may then be constrained in a variety ofconfigurations. For example, the membrane may be compressed onto amandrel such that the tubular membrane is compressed along a shorterlength, tending to create annular ridges or corrugations along thelength of the membrane.

Once the membrane is constrained into the desired shape, the membranemay be heated while constrained. After heating and cooling, the membranemay tend to retain the constrained shape. A tubular membrane set in acorrugated shape may exhibit elasticity between the ends of the membranedue to the corrugation. When pulled in the axial direction (opposite thedirection the membrane was compressed prior to heat-setting) thenreleased, the membrane will tend to return to the heat-set corrugatedconfiguration.

Furthermore, in the case of a corrugated tubular membrane, corrugationsmay facilitate bending of the membrane. Specifically, the annularcorrugations may both reinforce the membrane and provide elasticity suchthat the membrane can bend in a variety of configurations withoutkinking.

Multilayered constructs comprising corrugated or otherwise heat-setcomponents are within the scope of this disclosure. For example, atubular graft may comprise a corrugated tube coupled to a second tubehaving a relatively smooth wall (with respect to the corrugated tube).The tubes may overlap and be coaxial. In some embodiments a constructwill be configured with a smooth wall tube defining an inside diameter(which may be a blood contacting surface) and a corrugated tube definingan outside diameter (to provide support to the construct). As usedherein, a smooth wall component refers to a component without visuallyapparent surface defects or irregularities.

EXAMPLES

A number of exemplary PTFE mats were produced according to theelectrospinning disclosure above. FIGS. 12A-14B are SEMs of the PTFEmats produced in each exemplary process. FIGS. 15-16 are graphscomparing materials electrospun according to the present disclosure withother materials. Finally, FIG. 17 is a trichrome-stained histology lightmicroscopy image of an electrospun PTFE material. The following examplesare intended to further illustrate exemplary embodiments and are notintended to limit the scope of the disclosure.

Example 1

An experimental apparatus was assembled inside a ventilated hood. Theexperimental apparatus comprised a KD Scientific motorized syringe pump,a 10 ml syringe fitted with a 25 gauge metal syringe tip, and a SpellmanCZE 1000R high voltage source. The positive lead of the high voltagesource was connected to the metal syringe tip. The negative lead of thehigh voltage source was connected to a metal collector mounted about 7inches from the syringe tip.

Polymer solution was prepared by obtaining a 60 wt % PTFE aqueousdispersion. Crystalline PEO with an average chain molecular weight ofapproximately 300,000 was used. The PEO was mixed with water in anapproximately 30 wt % concentration and mixed until substantiallyhomogeneous. The 60 wt % PTFE dispersion was added to the PEO/watermixture to create five concentrations: a 0.016 g/ml mixture of PEO toPTFE dispersion, a 0.02 g/ml mixture of PEO to PTFE dispersion, a 0.032g/ml mixture of PEO to PTFE dispersion, a 0.04 g/ml mixture of PEO toPTFE dispersion, and a 0.048 g/ml mixture of PEO to PTFE dispersion.(Additionally, 35 ml of a 0.05 g/ml mixture of PEO to PTFE dispersionwas obtained by adding 5 ml of water to 1.4 grams of PEO which was thenmixed with 30 ml of PTFE dispersion. This concentration was not directlytested.) The PTFE/PEO/water combination was then mixed untilsubstantially homogeneous. The resulting mixture was strained through a70 micrometer nylon cell strainer to remove any remaining clumps in themixture.

Each polymer solution was separately loaded into the syringe, and thesyringe pump configured to dispense 0.01 ml of solution per minute. Thesyringe pump was activated and the high voltage power source turned onat 15,000 kV. The solution was forced through the syringe tip, where itwas electrically charged and pulled in a small diameter fiber toward thecollector. The process was run for approximately 15 minutes for eachpolymer solution, and the collector removed and sintered after runningeach solution. The collector and thin mat of fibers was sintered in anoven at 385 degrees C. for about 10 minutes. The resulting mat wasremoved and the collector used for the next solution. Each sintered matwas analyzed using a JEOL JSM-6510LV Scanning Electron Micrograph.

FIGS. 12A-12E are SEMs of the five fiber mats corresponding to the fivepolymer solutions spun in this example. Each SEM is at 950×magnification. FIG. 12A corresponds to the 0.016 g/ml mixture, FIG. 12Bto the 0.02 g/ml mixture, FIG. 12C to the 0.032 g/ml mixture, FIG. 12Dto the 0.04 g/ml mixture, and FIG. 12E to the 0.048 g/ml mixture.

It was observed that, in this example, the concentration of PEO to PTFEdispersion appeared to affect fiber formation on the mat. Both fiberdiameter and the presence of “beads” within the fibers appeared affectedby the concentration. Solutions with low concentrations (less than about0.02 g/ml) produced beading that may have been due to “sputtering” asthe solution left the syringe. Again, the resultant fiber mats are shownin FIGS. 12A-12E. Additionally, it was observed that solutions with lessthan about 0.015 g of PEO per ml of PTFE dispersion did not tend to formfibers, and solutions with greater than 0.06 g/ml concentrations tendedto dry in the syringe prior to electrospinning, creating macroscopicdefects in the mats.

In some embodiments, a construction comprised at least partially ofbeaded fibers may be incorporated into a stent covering or graft. Forexample, beaded fibers may increase endothelial attachment in someinstances. Thus, electrospun PTFE beaded fibers, such as those shown inFIGS. 12A and 12B, may be utilized in some constructions. As discussedabove, beading may occur with mixtures from about 0.010 g/ml to about0.018 g/ml of PEO per ml of PTFE.

Example 2

The apparatus described in Example 1 was again utilized to electrospineight additional solutions in connection with this Example.Substantially the same procedures described above were followed.However, additional water was added to the PEO-water mixture prior tomixing with the PTFE dispersions. The additional water appeared tofacilitate electrospinning of a greater range of PEO to PTFE dispersionconcentrations, while minimizing beading and sputtering. FIGS. 13A-13Hare SEMs corresponding to eight different concentrations with additionalwater added. Each SEM is at 950× magnification. FIG. 13A corresponds toa concentration of 0.0256 g/ml of PEO to PTFE dispersion, FIG. 13B to aconcentration of 0.030 g/ml, FIG. 13C to a concentration of 0.035 g/ml,FIG. 13D to a concentration of 0.040 g/ml, FIG. 13E to a concentrationof 0.045 g/ml, FIG. 13F to a concentration of 0.050 g/ml, FIG. 13G to aconcentration of 0.060 g/ml, and FIG. 13H to a concentration of 0.070g/ml.

It was observed that the additional water enabled bead-freeelectrospinning of a wider range of concentrations than was seen inExample 1. In the solution of FIG. 13C, it was observed that the PEO didnot fully evolve during the sintering process. This effect was not seenin connection with the solutions of Example 1; however, it was rare inconnection with the solutions of Example 2.

Example 3

The apparatus described in Example 1 was again utilized to electrospinan FEP/PEO dispersion. The polymer solution was prepared by obtaining a55 wt % FEP aqueous dispersion. Crystalline PEO with an average chainmolecular weight of approximately 300,000 was used. The PEO was mixedwith water in an approximately 30 wt % concentration and mixed untilsubstantially homogenous. The 55 wt % FEP dispersion was added to thePEO/water mixture to create a 0.06 g/ml mixture of PEO to FEPdispersion. The FEP/PEO/water combination was then mixed untilsubstantially homogeneous. The resulting mixture was strained through a70 micrometer nylon cell strainer to remove any remaining clumps in themixture.

The polymer solution was loaded into the syringe and the syringe pumpwas configured to dispense 0.01 ml of solution per minute. A sinteredtube of electrospun 0.048 g/ml PTFE to PEO from Example 1 was placedover the collector. The syringe pump was activated and the high voltagepower source turned on at 15,000 kV. The solution was forced through thesyringe tip, where it was electrically charged and pulled in a smalldiameter fiber toward the collector. The electrospun FEP fibers werecollected on top of the sintered PTFE tube. The process was run forapproximately 15 minutes and the collector was removed and heated to 325degrees C. for 10 minutes. The collection and the heating processes wererepeated one time to increase the thickness of the covering. Theresulting mat was removed from the collector. The cooked FEP mat wasanalyzed using a JEOL JSM-6510LV Scanning Electron Micrograph.

FIGS. 14A and 14B are SEMs of the cooked electrospun FEP over theelectrospun PTFE. FIG. 14A is at 180× magnification and FIG. 14B is at950× magnification.

It was observed in this example that upon heating, the electrospun FEPfibers would melt, creating a semi-porous coating over the electrospunPTFE fibers. In other examples, the porosity could be increased ordecreased by increasing or decreasing, respectively, the amount of timethe FEP is electrospun onto the PTFE fibers. Additionally, changing theheating temperature may also affect the porosity of the cooked FEPlayer. For example, the higher the temperature, the more the FEP maytend to flow and fill in voids. In some embodiments, an impervious layermay be created by repeated electrospinning of an FEP layer. This type ofcoating could additionally be used to create a secondary porosity forhydrophobic or hydrophilic properties as well as a porous coatingconfigured to screen for ingrowth cells based on cell size. Furthermore,the construct of this example exhibited an increase in tensile strengthas well as elasticity over the electrospun PTFE alone.

Example 4: Dip Coating

Multilayered constructs may be formed in some embodiments by dip coatingan electrospun or other material. In some embodiments, cracking of thedip coating may be reduced by reducing the thickness of the dipsolution.

For example, a PTFE layer was dip coated on a construct by adding 20 mlof water to 50 ml of a 60 wt % PTFE dispersion to thin the dispersion. Afiber mat was then dipped in the solution to coat the mat. The dip coatwas then sintered at 385 degrees C. for 15 minutes.

An FEP layer was dip coated on a construct by adding 20 ml of water to50 ml of a 55 wt % dispersion to thin the dispersion. A fiber mat wasthen dipped in the solution to coat the mat. The dip coat was thencooked at 325 degrees C. for 15 minutes.

In other embodiments, more or less water, for example from about 10 mlto about 50 ml, may be added to similar amounts and concentrations ofdispersion to thin the dispersion. Additionally, substances other than,or in addition to, water may be used to thin a dispersion for dipcoating. For example, a surfactant or a solvent may be used. In somesuch cases the surfactant or solvent may later be removed from theconstruct, including embodiments where it is allowed to evaporate whenthe coat is sintered or cooked. Alcohols, glycols, ethers, and so forthmay be so utilized.

Example 5: Endothelial Cell Attachment Assay

In some embodiments, the degree of endothelial cell attachment to amaterial may be determined according to the following assay. As usedherein, values for “in vitro endothelial cell attachment” are determinedby following the procedure disclosed below.

In this assay, the capacity of PTFE sample materials were tested todetermine their ability to support the growth and/or attachment ofporcine aortic endothelial cells. The PTFE materials comprisedelectrospun PTFE fiber mats spun from a 0.032 g/ml solution similar tothat described in connection with FIG. 12C and Example 1. A standardcurve with a range of endothelial cell seeding densities was generatedto correlate cell attachment with PTFE materials.

First, the PTFE materials and Beem capsules were ethylene oxide (ETO)sterilized. The Beem capsules were assembled with PTFE materials in anaseptic field.

An endothelial cell standard curve was prepared in a 96 well plate withduplicate wells for 0, 2.5K, 5K, 10K, 20K, 40K, 60K, and 80K endothelialcells per well in 200 μl total volume of media. The endothelial cellswere allowed to attach 90 minutes at 37° C. in 5% CO₂. At 90 minutes, 20μl of 5 mg/ml MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-DiphenyltetrazoliumBromide) was added to each well and incubated at 37° C. in 5% CO₂ for 3hours. The assembly was inverted and the 96 well was gently rapped on anabsorbent bench coat to remove media and unattached cells.

Actively respiring cells convert the MTT to an intracellular purpleformazan product. Thus, after the incubation period, intracellularformazan must be solubilized by isopropanol. 200 μl of 100% isopropanolwas added to wells in the 96 well plate, which was incubated at roomtemperature for 30 minutes. The solution in each well was then mixed bypipeting. 100 μl of supernatant from the endothelial cell standard wellswere transferred to clean wells in 96-well clear-bottomed plate. Theoptical density (OD) was read at 560 nm and 650 nm. The backgroundabsorbance at 650 nm was subtracted from the 560 nm absorbance and theresults, minus control, were graphed.

As used herein, “optical density” (OD) measures the absorbance of lightin the solution. In this example, the greater the number of cells whichattach to the material, and are available to react with the MTT, thegreater the amount of formazan generated within the cell, the darker thecolor of purple formazan extracted into the supernatant, and, therefore,the higher the OD (or absorbance of light). Assuming that all the cellsin the experiment convert MTT to its formazan derivative at the samerate, the OD measurement is directly proportional to the number ofattached cells.

The PTFE materials in Beem capsules were pre-wet with 200 μl of D-PBS(Dulbecco's phosphate buffered saline) and incubated at 37° C. in 5% CO2for 50 minutes. The D-PBS was removed from the Beem capsules. The Beemcapsules were then seeded with 50K endothelial cells in 200 μl ofcomplete media, with the exception of a Beem control capsule for eachtest material, which contained complete media only (no cells). Themedia-only Beem capsule controls were processed identically as the Beemcapsules seeded with endothelial cells. The endothelial cells wereallowed to attach 90 minutes at 37° C. in 5% CO₂. At 90 minutes, 20 μlof 5 mg/ml MTT ((3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) was added to each Beem capsule, including controls, andincubated at 37° C. in 5% CO₂ for 3 hours. The Beem capsules wereinverted and gently rapped on an absorbent bench coat to remove mediaand unattached cells.

The PTFE materials were carefully removed from Beem assemblies andplaced in a microcentrifuge tube containing 200 μl of 100% isopropanolfor 30 minutes. The microcentrifuge tubes were then vortexed with thePTFE materials and isopropanol for 3-5 minutes to release formazan intothe supernatant. 100 μl of supernatant from the microcentrifuge tubeswere transferred to clean wells in 96-well clear-bottomed plate (thesame plate with the standards, described above). The OD was read at 560nm and 650 nm. The background absorbance at 650 nm was subtracted fromthe 560 nm absorbance and the results, minus control were analyzed. Thenumber of cells attached to each sample was interpolated from thestandard curve results. As described in the standard curve wellsoutlined above, the MTT formazan was produced in proportion to thenumber of attached live cells within each capsule.

A standard curve of porcine endothelial cells was prepared for eachunique assay of test materials and run in parallel with the materials inBeem capsules. In addition to electrospun samples, commercial expandedPTFE (ePTFE) material samples were also tested to provide a reference orcomparison for the electrospun materials. The control ePTFE materialused was the commercially available Bard Impra Straight ThinwallVascular Graft (Cat #80S06TW), which is often used as a control materialin relevant literature as it is known to have a favorable biologicresponse and favorable endothelial cell attachment.

To quantify the measurements obtained for the test materials, a standardcurve was generated by measuring the optical density using the wellsknown to contain 0, 2.5K, 5K, 10K, 20K, 40K, 60K, and 80K endothelialcells per well. Using the generated standard curve, the number ofattached cells in the experimental wells was then calculated.

The materials disclosed herein may be configured to achieve variousamounts of in vitro endothelial cell attachment as defined by thisassay. As described above, changes to the percent porosity of a mat, thethickness of the mat, and/or the diameter of fibers comprising the matmay influence the characteristics of the mat, including the response ofthe material to this assay. Thus, the number of cells attached to theelectrospun materials were compared by normalizing the results to thenumber of cells attached the ePTFE control material. The endothelialcell attachment for the electrospun material assayed was greater that170% of the endothelial cell attachment of the ePTFE control material.Materials within the scope of this disclosure may have in vitroendothelial cell attachments of 170%, more than 170%, or less than 170%of an ePTFE control material. For example, from 30% to more than 170% ofthe endothelial cell attachment of an ePTFE control material, includingmore than 30%, more than 40%, more than 50%, more than 75%, more than100%, more than 125%, more than 150%, more than 160%, more than 165%,and more than 170% of the endothelial cell attachment of an ePTFEcontrol material.

Example 6: Rodent Study

In this example, the biocompatibility response of an electrospun polymerfiber-coated material was compared against commercially-available ePTFEgrafts and similar constructs. Eleven rodents were each subcutaneouslyimplanted with a pledget of polymer material, the pledget obtained usinga 2-4 mm biopsy punch. Two rodents were implanted with an electrospunfiber coated PTFE labeled MM1 E. This material was obtained byelectrospinning a 0.032 g/ml solution, similar to that discussed inExample 5. The implanted material comprised a layered construct, with anFEP film disposed between two layers of electrospun PTFE coating. Tworodents were implanted with portions of a commercially available ePTFEstent graft material labeled ePTFE Sample 1, one rodent with the insidediameter (ID) material and one with the outside diameter (OD) material.Likewise, two rodents were implanted with inside and outside diametermaterials from a commercially available ePTFE stent graft materiallabeled ePTFE Sample 2. Two rodents were implanted with inside andoutside diameter materials from a commercially available heparinsurface-coated ePTFE stent graft material labeled ePTFE Sample 3. Tworodents were implanted with inside and outside diameter materials froman ePTFE vascular graft material labeled ePTFE Sample 4. ePTFE samples 1to 4 are a representative sampling of commercially available ePTFEstents and vascular grafts. Finally, one rodent was implanted with aportion of an ePTFE stent graft material labeled Control ePTFE. Thissample is a commercially available ePTFE material produced by Bard whichis often used as a control material in relevant literature.

After two weeks of implantation the implanted samples were analyzed forinflammation and cellular penetration. Specifically, pledgets of each ofthe above materials were cut or punched prior to surgery. Materials wereETO sterilized. On the day of surgery, subjects were prepped for sterilesurgical procedures. Each subject was ear tagged for unique studyidentification and for the ability to evaluate subjects based on subjectnumber to maintain an investigator-blinded analysis of the data, priorto de-coding the data.

At the end of the two-week implantation period, all subjects wereeuthanized and implanted materials and surrounding tissue wereexplanted. The explants were immediately placed into 2% paraformaldehydefixative for up to 48 hours and then changed into a 70% ethanol solutionfor subsequent processing for paraffin embedding. Tissue blocks wereprocessed for histology and immunohistochemistry then stained withhematoxylin and eosin or trichrome stain or reacted with antibodies forvWF (an endothelial cell marker) and CD-68 (a marker for activatedmacrophages). All slides that were subjectively evaluated were digitallyscanned using the Aperio ScanScope CS system. Inflammatory response andcellular penetration into the material were quantified as describedbelow.

A. Inflammatory Response

The inflammatory responses towards the various implanted PTFE materialswere compared. The outer diameter (OD) and the inner diameter (ID) ofthe material were separately characterized. To quantify the inflammatoryresponse, an established equation was used to provide weight to stainingintensities and provide a quantitative value to the macrophage counts.The equation was based on equations currently used by pathologists incancer research called the H-score (Nakopoulou et al., Human Pathologyvol. 30, no. 4, April 1999). The H-score was obtained by the formula:

(3×percentage of strongly staining nuclei)+(2×percentage of moderatelystaining nuclei)+(percentage of weakly staining nuclei)=a range of 0 to300

Strongly staining nuclei were represented by red in a false colormark-up in a digital algorithm, moderately stained nuclei wererepresented by orange in the false color mark-up, and weakly stainednuclei were represented by yellow. By inserting these counts into theformula above, a quantitative inflammatory response is obtained. Aone-way ANOVA analysis with a Tukey post-hoc test (p<0.05) was used toassess statistical differences.

FIG. 15 illustrates the inflammatory response caused by the variousmaterials as quantified by H-Score. Qualitatively, most materials werefound to be moderately reactive with an average inflammatory scorebetween 101 to 200, with scores over 250 considered inflammatory. Thepresent electrospun PTFE material (MM1 E), both OD and ID and the ePTFESample 1 OD material had inflammatory H-scores measuring below 150.Materials found to be strongly reactive with inflammatory scores wellabove 150, such as 201 to 300 were the ePTFE Sample 1 ID and ePTFESample 3 ID materials. The difference between the lower H-Scores and thehigher H-scores was statistically significant. The relatively lowresponse of ePTFE Sample 1 OD was counteracted by the high response seenon the ID of the same sample.

Lower inflammation in response to the MM1 E material indicates that itis less hostile to surrounding biological tissue. MM1 E is the onlymaterial that showed significantly lower inflammatory response on boththe OD and ID, both of which would be exposed to biological cells andtissue during use as a stent coating. More specifically, the OD isadjacent the endothelial layer of a blood vessel and the ID is incontact with blood cells. These results indicate that MM1 E is morebiocompatible than other available materials.

B. Cellular Penetration

The ability of cells to penetrate the material from both the inner toouter surfaces and the outer to inner surfaces was measured and definedas cellular penetration. More specifically, cellular penetration as apercentage of PTFE material thickness was determined by performingmeasurements of the material thickness at 100 μm intervals and measuringthe depth of cellular penetration from the superficial surface towardsthe midline. The percent of cellular penetration was measured from thesuperficial sides (from inner surface and from outer surface) of thematerial. A one-way ANOVA analysis with a Tukey post-hoc test (p<0.05)was used to assess statistical differences between groups.

This analysis demonstrated that all materials tested had some degree ofcellular penetration meaning that cells were able to migrate into thearchitecture of the PTFE construct. As shown in FIG. 16, the MM1 E-IDand VT-ID materials were found to be statistically different from eachother. However, relevant trends were observed from the remainder. Thisgraph demonstrates that various PTFE materials/devices may havedifferent cellular ingrowth. For example, both the MM1 E and FluencyPTFE materials (both OD and ID) demonstrated a tendency towardspromoting a greater amount of cellular penetration.

Of particular relevance, the MM1 E material was unique in that itappeared to encourage the greatest cellular penetration whencharacterized from the edge of the material (superficial side) across tothe middle layer. Both the MM1 E-OD and MM1 E-ID constructs had greaterthan 80% migration of cells to the relatively impermeable middle layer.FIG. 17 shows how cells migrate through the outer (OD) and inner (ID)layers, but most cannot penetrate the middle layer. Specifically, thedotted lines in FIG. 17 indicate the middle layer of the construct. Thelack of dark spots (stained cells) in this zone reflects a lack ofcellular migration or cellular penetration into this zone. The areasimmediately adjacent the middle zone are the outer and inner layers, oneof which is indicated by the double headed arrow. The dark spots inthese zones reflect cellular penetration into these more porous portionsof the construct.

EXEMPLARY EMBODIMENTS

The following embodiments are illustrative and exemplary and not meantas a limitation of the scope of the present disclosure in any way.

I. Medical Appliance

In one embodiment a medical appliance comprises a first layer ofelectrospun polytetrafluoroethylene (PTFE), having an average percentporosity between about 30% and about 80%.

The electrospun PTFE may comprise a mat of PTFE nanofibers.

The electrospun PTFE may comprise a mat of PTFE microfibers.

The medical appliance may further comprise a second layer of electrospunPTFE nanofibers, wherein the first layer of electrospun PTFE is disposedsuch that it defines a first surface of the medical appliance, and thesecond layer of electrospun PTFE is disposed such that it defines asecond surface of the medical appliance.

In some embodiments, the first layer of electrospun PTFE has an averagepercent porosity between about 35% and about 70%.

In other embodiments, the first layer of electrospun PTFE has an averagepercent porosity of between about 40% and about 60%.

The first layer of electrospun PTFE may have an average pore sizeconfigured to permit tissue ingrowth on the first surface of the medicalappliance.

The first layer of electrospun PTFE may permit tissue ingrowth.

The second layer of electrospun PTFE may have an average percentporosity of about 50% or less.

The second layer of electrospun PTFE may have an average pore sizeconfigured to resist tissue ingrowth into or through the second surfaceof the medical appliance.

The medical appliance may also further comprise a cuff adjacent to anend of the medical appliance, the cuff configured to permit tissueingrowth into or tissue attachment to the cuff.

The medical appliance may further include a tie layer disposed betweenthe first layer of electrospun PTFE and the second layer of electrospunPTFE.

The tie layer may be configured to inhibit tissue ingrowth into orthrough the tie layer.

The first and second layers of electrospun PTFE and the tie layer may beconfigured to inhibit an unfavorable inflammatory response.

The first and second layers of electrospun PTFE material may haveinflammatory H-scores measuring below about 150.

The first and second layers of electrospun PTFE material may beconfigured to allow an average cellular penetration of over 20%.

The first and second layers of electrospun PTFE and the tie layer may beconfigured to inhibit hyperplastic tissue growth including neointimal orpseudointimal hyperplasia.

The tie layer may comprise PTFE.

The tie layer may comprise a thermoplastic polymer.

The tie layer may comprise fluorinated ethylene propylene (FEP).

The tie layer may comprise electrospun FEP.

The electrospun FEP layer may be cooked.

The electrospun FEP layer may be configured to resist cellular ingrowth.

The electrospun FEP layer may be substantially impervious to cellularingrowth.

The electrospun FEP layer may be substantially non-porous.

The electrospun FEP layer may be substantially porous.

The FEP may partially bond to the nanofibers of the first and secondlayers of electrospun PTFE.

The FEP may flow into and coat the nanofibers of the first and secondlayers of electrospun PTFE.

The FEP may coat the nanofibers of the first and second layers whilemaintaining the porosity of the layers.

The electrospun PTFE may be formed from a mixture comprising PTFE,polyethylene oxide (PEO), and water.

The mixture may be formed by combining a PTFE dispersion with PEOdissolved in water.

The mixture may comprise between about 0.02 and about 0.070 grams of PEOper ml of 60 wt % PTFE aqueous dispersion.

The medical appliance may further comprise a main lumen extending to abifurcation and two branch lumens extending from the bifurcation.

The medical appliance may further comprise a main lumen and one or morebranch lumens extending from a wall of the main lumen.

The electrospun PTFE may comprise a mat of beaded PTFE fibers.

At least one of the first and second layers of electrospun PTFE may havebeen heated and stretched after sintering.

The medical appliance may further comprise a reinforcing layer.

The reinforcing layer may comprise electrospun PTFE.

The reinforcing layer may have greater tensile strength in a firstdirection of the layer than in a second direction perpendicular to thefirst direction.

The medical appliance may comprise a tubular construct.

The reinforcing layer may comprise a tube disposed such that the firstdirection is in the axial direction of the tubular construct.

The reinforcing layer may comprise a strip wrapped helically around aportion of the tubular construct.

The medical appliance may have increased resistance to creep in theradial direction as compared to the axial direction.

II. Stents

In one embodiment, a stent comprises a frame configured to resist radialcompression when disposed in a lumen of a patient, and a coveringdisposed on at least a portion of the scaffolding structure, thecovering comprising a first layer of electrospun polytetrafluoroethylene(PTFE), the first layer having a percent porosity between about 30% andabout 80%.

The electrospun PTFE may comprise a mat of PTFE nanofibers and/or PTFEmicrofibers.

The stent may further comprise a second layer of electrospun PTFEnanofibers, wherein the stent is generally tubular in shape and thefirst layer of electrospun PTFE is disposed such that it defines aninside surface of the stent and the second layer of electrospun PTFE isdisposed such that it defines an outside surface of the stent.

In such an embodiment, the first layer of electrospun PTFE may have anaverage percent porosity between about 35% and about 70%.

The first layer of electrospun PTFE may have an average percent porosityof between about 40% and about 60%.

The first layer of electrospun PTFE may have an average pore sizeconfigured to permit tissue ingrowth on the inside surface of the stent.

The first layer of electrospun PTFE may permit tissue ingrowth.

The second layer of electrospun PTFE may have an average percentporosity of about 50% or less.

The second layer of electrospun PTFE may have an average pore sizeconfigured to resist tissue ingrowth into or through the second layer ofelectrospun PTFE.

The stent may further comprise a cuff adjacent to an end of the stent,the cuff configured to permit tissue ingrowth into the cuff.

A tie layer may be disposed between the first layer of electrospun PTFEand the second layer of electrospun PTFE.

The tie layer may be configured to inhibit tissue ingrowth into the tielayer.

The tie layer may comprise PTFE.

The tie layer may be a thermoplastic polymer.

The tie layer may be fluorinated ethylene propylene (FEP).

The tie layer may be electrospun FEP.

The electrospun FEP layer may be cooked.

The electrospun FEP layer may be configured to resist cellular ingrowth.

The electrospun FEP layer may be substantially impervious to cellularingrowth.

The electrospun FEP layer may be substantially non-porous.

The electrospun FEP layer may be porous.

The FEP may partially bond to the nanofibers of the first and secondlayers of electrospun PTFE.

The second layer of electrospun PTFE material may be configured topermit tissue ingrowth into the second layer to reduce device migration.

The first and second layers of electrospun PTFE and the tie layer may beconfigured to inhibit hyperplastic tissue growth such as neointimal orpsuedointimal hyperplasia.

The first and second layers of electrospun PTFE and the tie layer may beconfigured to inhibit an unfavorable inflammatory response.

The first and second layers of electrospun PTFE material haveinflammatory H-scores measuring below about 150.

The first and second layers of electrospun PTFE material may beconfigured to allow an average cellular penetration of over 20%.

The FEP may flow into and coat the nanofibers of the first and secondlayers of electrospun PTFE.

The FEP may coat the nanofibers of the first and second layers whilemaintaining the porosity of the layers.

The electrospun PTFE may be formed from a mixture comprising PTFE,polyethylene oxide (PEO), and water.

The mixture may be formed by combining a PTFE dispersion with PEOdissolved in water.

The electrospun PTFE may be electrospun onto a rotating mandrel.

The mixture may comprise between about 0.02 and about 0.070 grams of PEOper ml of 60 wt % PTFE aqueous dispersion.

The frame of the stent may be comprised of a single wire.

The wire may be helically wound around a central axis of the stent.

The wire may have a wave-like pattern defining apexes and arms.

Alternating apexes adjacent an end of the stent may have differentrelative heights.

Each apex may have a radius of between about 0.12 mm and 0.64 mm.

The stent may have a first portion disposed near the midbody of thestent and second and third portions disposed near the ends of the stent,and wherein the arms disposed within the second and third portions arerelatively longer than the arms disposed within the first portion.

Moreover, a distance, apex to apex length, may be defined as thedistance between a first apex and a second apex wherein the first apexlies on a first coil of wire and the second apex lies on a second coilof wire adjacent to the first coil, and wherein the first apex and thesecond apex lies substantially on a line on the outer surface of thestent, the line being co-planar with and parallel to a central axis ofthe stent, wherein the apex to apex distance is smaller at the midbodyof the stent, relative to the apex to apex distance near the ends of thestent.

The stent may be structured such that a midbody portion of the stent isrelatively less compressible than a first and a second end of the stent.

The stent may further comprise a main lumen extending to a bifurcationand two branch lumens extending from the bifurcation.

The stent may further comprise a main lumen and one or more branchlumens extending from a wall of the main lumen.

The electrospun PTFE may comprise a mat of beaded PTFE fibers.

III. Tubular Vascular Prosthesis

In one embodiment, a tubular vascular prosthesis comprises a porousinner layer, a porous outer layer, and a substantially non-porous tielayer disposed between the inner layer and the outer layer.

At least one of the inner layer and the outer layer may comprise anelectrospun material.

The tie layer may be substantially impervious to cellular ingrowth.

The inner and outer layers may be configured to permit cellularingrowth.

IV. Method of Constructing a Medical Appliance

In one embodiment, a method of constructing a medical appliancecomprises electrospinning a first tube of polytetrafluoroethylene (PTFE)onto a mandrel, the first tube having a percent porosity between about30% and about 80%, and sintering the first tube.

The first tube of PTFE may be electrospun onto a rotating mandrel.

The method may further comprise applying a second tube of electrospunPTFE around the first layer.

The method may further comprise applying a scaffolding structure aroundthe first tube, and applying a fluorinated ethylene propylene (FEP)layer around the first tube and the scaffolding structure, prior toapplying the second tube of electrospun PTFE.

The FEP layer may be configured to inhibit tissue ingrowth into orthrough the FEP layer.

The method may further comprise heating the medical appliance such thatthe FEP layer bonds to the first and second tubes.

The FEP may partially bond to the fibers of the first and second tubes.

The FEP may flow into and coat the fibers of the first and second tubes.

The FEP may coat the fibers of the first and second tubes whilemaintaining the porosity of the tubes.

The second tube of electrospun PTFE may be formed by a method comprisingelectrospinning the second tube of PTFE onto a rotating mandrel andsintering the second tube.

A compressive wrap may be applied around the second tube before themedical appliance is heat treated.

Electrospinning the first tube of PTFE may comprise mixing a PTFEdispersion with polyethylene oxide (PEO), wherein the PEO is dissolvedin water to form a mixture; and discharging the mixture from an orificeonto the rotating mandrel.

The mixture may comprise between about 0.02 and about 0.07 grams of PEOper ml of 60 wt % PTFE aqueous dispersion.

The mixture comprises between about 0.03 and about 0.04 grams of PEO perml of 60 wt % PTFE aqueous dispersion.

The method may further comprise coupling a cuff to an end of the medicalappliance, the cuff configured to permit tissue ingrowth into the cuff.

V. Method for Promoting Endothelial Cell Growth

In one embodiment, a method for promoting endothelial cell growth on animplantable medical appliance comprises implanting the medical applianceinto a patient, the medical appliance coated with at least oneelectrospun polymer layer having a percent porosity of between about 35%and about 70%, such that endothelial cells grow on or attach to thesurface of the at least one electrospun polymer layer.

The implantable medical appliance may comprise a stent.

The implantable medical appliance may comprise a graft.

The at least one electrospun polymer layer may comprise an electrospunPTFE layer.

The medical appliance may be coated with a second polymer layer thatinhibits tissue or fluid migration through the second polymer layer.

The second polymer layer may comprise an FEP layer.

The electrospun fibrous PTFE may comprise randomized microfibers ornanofibers.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 30% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 40% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 50% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 75% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 100% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 125% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 150% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 160% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 165% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The at least one polymer layer of the implanted medical appliance may beconfigured to permit at least 170% in vitro endothelial cell attachment,compared to an expanded PTFE control material.

The percent porosity of the electrospun polymer layer may be betweenabout 40% and about 60%.

The mandrel may comprise a main portion and two leg portions, the mainportion configured to coincide with a main lumen of a bifurcated medicalappliance and the two leg portions configured to coincide with the legportions of the bifurcated medical appliance.

The two leg portions of the mandrel may be removable from the mainportion of the mandrel.

The first tube may be electrospun by rotating the mandrel about an axisof the leg portions of the mandrel while electrospinning fibers androtating the mandrel about an axis of the main portion of the mandrelwhile electrospinning fibers.

VI. Method for Promoting Cellular Growth into an Implantable MedicalAppliance

In one embodiment, a method for promoting cellular growth into animplantable medical appliance comprises: obtaining a medical appliancecoated with at least one electrospun polymer layer having a percentporosity of between about 30% and about 80% and at least one layer thatis substantially impervious to cellular growth; and implanting themedical appliance into a patient such that the electrospun polymer layerof the medical appliance is in direct contact with body fluid or bodytissue.

The at least one electrospun polymer layer may comprise electrospunPTFE.

The electrospun PTFE material may be configured to permit at least 20%cellular penetration, in vivo two weeks after murine implantation.

V. Method for Inhibiting a Neointimal Hyperplasia Response

In one embodiment, a method for inhibiting a neointimal hyperplasiaresponse to an implantable medical appliance comprises implanting themedical appliance into a patient, the medical appliance coated with afirst electospun PTFE layer comprising a porous mat and a second polymerlayer that inhibits tissue ingrowth into or through the second polymerlayer.

The first electrospun polymer layer may permit endothelial cell growthor attachment on the surface of the first electrospun polymer layer.

The first electrospun polymer layer may comprise a fibrous PTFE layerand the second polymer layer may comprise an FEP layer.

The medical appliance may also be coated with a third polymer layercomprising an electrospun PTFE layer, such that the FEP layer isdisposed between the first and third polymer layers.

The first and third polymer layers may comprise an electrospunmicrofiber or nanofiber PTFE mat.

The second polymer layer may comprise an electrospun FEP mat.

VIII. Method for Inhibiting an Inflammatory Response

In one embodiment, a method for inhibiting an inflammatory response toan implantable medical appliance comprises implanting the medicalappliance into a patient, the medical appliance coated with a firstelectrospun polymer layer comprising a porous PTFE mat and a secondpolymer layer comprising FEP that inhibits tissue ingrowth into orthrough the second polymer layer.

The first electrospun polymer layer, when placed in vivo, may have anH-score of less than 150 two weeks after murine implantation.

While specific embodiments of stents and other medical appliances havebeen illustrated and described, it is to be understood that thedisclosure provided is not limited to the precise configuration andcomponents disclosed. Various modifications, changes, and variationsapparent to those of skill in the art having the benefit of thisdisclosure may be made in the arrangement, operation, and details of themethods and systems disclosed, with the aid of the present disclosure.

Without further elaboration, it is believed that one skilled in the artcan use the preceding description to utilize the present disclosure toits fullest extent. The examples and embodiments disclosed herein are tobe construed as merely illustrative and exemplary and not as alimitation of the scope of the present disclosure in any way. It will beapparent to those having skill in the art, and having the benefit ofthis disclosure, that changes may be made to the details of theabove-described embodiments without departing from the underlyingprinciples of the disclosure herein.

1. A covered stent, comprising: a frame comprising a midbody and a flarezone; and a cover coupled to the frame, wherein the cover comprises anelectrospun polytetrafluoroethylene (PTFE) material, and wherein theframe and the cover are configured to promote biocompatibility of thestent.
 2. The stent of claim 1, wherein the midbody comprises a firstapex to apex length, wherein the flare zone comprises a second apex toapex length, wherein the first apex to apex length is less than thesecond apex to apex length, and wherein a resistance to radialcompression of the midbody is greater than a resistance to radialcompression of the flare zone.
 3. The stent of claim 2, wherein theflare zone is configured to engage with healthy tissue of a blood vesseland minimize trauma to the healthy tissue.
 4. The stent of claim 2,wherein the first apex to apex length ranges from 2.0 mm to 30.0 mm, andwherein the second apex to apex length ranges from 2.1 mm to 30.1 mm. 5.The stent of claim 1, wherein an end of the flare zone comprises analternating pattern of long apexes and short apexes about a perimeter ofthe frame, wherein the alternating pattern is configured to distributean outwardly directed force along a length of a vessel wall, and whereinthe end of the flare zone is configured to be a-traumatic to healthytissue of the vessel wall.
 6. The stent of claim 1, wherein the coverincludes a scallop shaped end, wherein the scallop shaped end isconfigured to reduce infolding of tissue of a vessel wall when anoutside diameter of the stent is greater than an inside diameter of avessel.
 7. A covered stent, comprising: a frame; and a cover coupled tothe frame, wherein the cover comprises an electrospun PTFE material, andwherein an inner layer and an outer layer of the cover are eachconfigured to be cell permeable.
 8. The covered stent of claim 7,wherein the inner layer is configured to promote attachment of a coatingof epithelial cells, wherein the coating is configured to preventthrombosis within a lumen of the stent, and wherein the outer layer isconfigured to permit healing of tissue adjacent the stent.
 9. Thecovered stent of claim 7, wherein a porosity of the inner layer and aporosity of the outer layer each range from 30% to 80%.
 10. The coveredstent of claim 7, wherein an average pore size of the inner layer and anaverage pore size of the outer layer each range from 1 micron to 12microns.
 11. The covered stent of claim 7, wherein a thickness of theinner layer and a thickness of the outer layer each range from 20micrometers to 100 micrometers.
 12. The covered stent of claim 7,wherein the inner layer and the outer layer comprise a plurality offibers, and wherein an average diameter of the plurality of fibersranges from 50 nanometers to 3 micrometers.
 13. The covered stent ofclaim 7, wherein the inner layer and the outer layer are each configuredto allow an average cell penetration depth of greater than 98% of athickness of the layer.
 14. The covered stent of claim 7, wherein theinner layer and the outer layer are configured to produce an averagefibrous capsule thickness of less than 35 micrometers.
 15. The coveredstent of claim 7, wherein the cover is configured to filter blood,wherein the inner layer and the outer layer are configured to permittransmural migration of blood plasma and to prevent transmural migrationof red blood cells.
 16. The covered stent of claim 15, wherein a middlelayer is configured to prevent transmural migration of cells, andwherein the middle layer is configured to prevent restenosis of avessel.
 17. The stent of claim 16, wherein the middle layer isconfigured to prevent transmural fluid migration, and wherein the middlelayer is configured to contain a fluid within the stent.
 18. A method ofpromoting biocompatibility of a stent, comprising: promoting endothelialcell growth on a luminal surface of the stent; reducing a tissueinflammatory response to the stent; or resisting fibrous capsuleformation adjacent the stent; wherein the stent comprises a covercomprising an electrospun PTFE material, the cover comprising: aporosity ranging from 30% to 80%; an average pore size ranging from 1micron to 12 microns; a thickness ranging from 20 micrometers to 100micrometers; and a plurality of fibers having an average diameterranging from 50 nanometers to 3 micrometers.
 19. The method of claim 18,wherein promoting endothelial cell growth comprises reducing turbulentflow within the stent.
 20. The method of claim 18, wherein reducing aninflammatory response comprises reducing macrophage and foreign bodygiant cell counts adjacent the stent.
 21. The method of claim 20,wherein reducing macrophage and foreign body giant cell counts isconfigured to comprises an H-score of less than
 100. 22. The method ofclaim 18, wherein resisting fibrous capsule formation comprises afibrous capsule having a thickness of any one of less than 35micrometers, less than 30 micrometers, less than 25 micrometers, lessthan 20 micrometers, and less than 15 micrometers.